Tetrahydro[1,8]naphthyridine sulfonamide and related compounds for use as agonists of RORy and the treatment of disease

ABSTRACT

The invention provides tetrahydro[1,8]naphthyridine and related compounds, pharmaceutical compositions, methods of promoting RORγ activity, increasing the amount of IL-17 in a subject, and treating cancer using such tetrahydro[1,8]naphthyridine and related compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.14/398,774, filed Nov. 4, 2014, which is the national stage ofInternational (PCT) Patent Application Serial No. PCT/US2013/040085,filed May 8, 2013, and published under PCT Article 21(2) in English,which claims the benefit of and priority to United States ProvisionalPatent Application Ser. No. 61/644,104, filed May 8, 2012, the contentsof each of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The invention provides tetrahydro[1,8]naphthyridine and relatedcompounds, methods of promoting RORγ activity and/or increasing theamount of IL-17 in a subject, and therapeutic uses of thetetrahydro[1,8]naphthyridine and related compounds. In particular, theinvention provides sulfonamide-tetrahydro[1,8]naphthyridine and relatedcompounds, methods of using such compounds to promote RORγ activityand/or increase the amount of IL-17 in a subject, and treat medicalconditions in which activation of immune response would be beneficialsuch as in cancer and infections.

BACKGROUND OF THE INVENTION

Retinoid-related orphan receptors (ROR) are reported to have animportant role in numerous biological processes. See, for example,Dussault et al. in Mech. Dev. (1998) vol. 70, 147-153; and Andre et al.in EMBO J. (1998) vol. 17, 3867-3877. Scientific investigations relatingto each of retinoid-related orphan receptors RORα, RORβ, and RORγ havebeen described in the literature. See, for example, Hirose et al. inBiochem. Biophys. Res. Commun. (1994) vol. 205, 1976-1983; Giguere etal. in Genes. Dev. (1994) vol. 8, 538-553; Medvedev et al. in Gene(1996) vol. 181, 199-206; Ortiz et al. in Mol. Endocrinol. (1995) vol.9, 1679-1691; Jetten A M in Curr Drug Targets Inflamm Allergy (2004)vol. 3, 395-412). Continuing research in this field is spurred by thepromise of developing new therapeutic agents to treat medical disordersassociated with retinoid-related orphan receptor activity.

RORγ has been reported to be expressed in high concentration in varioustissues, such as thymus, kidney, liver, muscle, and certain fat tissue.See, for example, Hirose et al. in Biochem. Biophys. Res. Commun. (1994)vol. 205, 1976-1983; Medvedev et al. in Gene (1996) vol. 181, 199-206;Ortiz et al. in Mol. Endocrinol. (1995) vol. 9, 1679-1691; and He et al.in Immunity (1998) vol. 9, 797-806. Two isoforms of RORγ have beenidentified and are referred to as γ1 and γ2 (also referred to as RORγt).See, for example, He et al. in Immunity (1998) vol. 9, 797-806.Expression of the γ2 isoform has been reported to appear in, forexample, double-positive thymocytes. See, for example, He et al. inImmunity (1998) vol. 9, 797-806; and Villey et al. in Eur. J. Immunol.(1999) vol. 29, 4072-4080. RORγt plays a critical role in regulatingdifferentiation of Th17 cells, a subset of T helper lymphocytes. See,for example, Ivanov et al. in Cell (2006) vol. 126, 1121-1133. Th17cells are important for recruiting tumor-killing cytotoxic CD8+ T cellsand natural killer cells into the tumor microenvironment. The level ofTh17 cells correlated positively with patient survival or slower diseaseprogression in certain cancers. See, for example, Kryczek et al. inBlood (2009) vol 114, 1141-1149; and Sfanos et al. in Clinical CancerResearch (2008) vol 14, 3254-3261. Compounds capable of enhancing RORγtactivity are thus contemplated to provide a therapeutic benefit in thetreatment of cancer.

Cancer continues to be a significant health problem despite thesubstantial research efforts and scientific advances reported in theliterature for treating this disease. Some of the most frequentlydiagnosed cancers include prostate cancer, breast cancer, and lungcancer. Prostate cancer is the most common form of cancer in men. Breastcancer remains a leading cause of death in women. Current treatmentoptions for these cancers are not effective for all patients and/or canhave substantial adverse side effects.

Accordingly, a need exists for improved treatments for cancer. Thepresent invention addresses this need and provides other relatedadvantages.

SUMMARY

The invention provides 1,8-tetrahydro[1,8]naphthyridine and relatedcompounds, pharmaceutical compositions, methods of promoting RORγactivity and/or increasing the amount of IL-17 in a subject, and methodsof treating various medical disorders using such compounds. Inparticular, one aspect of the invention provides a collection oftetrahydro[1,8]naphthyridine and related compounds, such as a compoundrepresented by Formula I:

or a pharmaceutically acceptable salt or solvate thereof; wherein thevariables are as defined in the detailed description. Furtherdescription of additional collections of tetrahydro[1,8]naphthyridineand related compounds, such as Formulae II-V, are described in thedetailed description.

Another aspect of the invention provides a method of treating a subjectsuffering from a medical disorder. The method comprises administering tothe subject a therapeutically effective amount of one or moretetrahydro[1,8]naphthyridine or related compounds described herein,e.g., a compound of Formula I, II, III, IV, or V, wherein Formulae I-Vare as described in the detailed description. A large number ofdisorders can be treated using the tetrahydro[1,8]naphthyridine andrelated compounds described herein. For example, the compounds describedherein can be used to treat cancer, a bacterial infection, a fungalinfection, or an immune deficiency disorder.

Another aspect of the invention provides a method of promoting theactivity of RORγ. The method comprises exposing a RORγ to an effectiveamount of one or more tetrahydro[1,8]naphthyridine or related compoundsdescribed herein, e.g., a compound of Formula I, II, III, IV, or V, or apharmaceutical composition described herein.

Another aspect of the invention provides a method of increasing theamount of IL-17 in a subject. The method comprises administering to asubject an effective amount of one or more tetrahydro[1,8]naphthyridineor related compounds described herein, e.g., a compound of Formula I,II, III, IV, or V, or a pharmaceutical composition described herein, toincrease the amount of IL-17 in the subject.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides tetrahydro[1,8]naphthyridine and relatedcompounds, pharmaceutical compositions, methods of promoting RORγactivity and/or increasing the amount of IL-17 in a subject, andtherapeutic uses of the tetrahydro[1,8]naphthyridine and relatedcompounds. The practice of the present invention employs, unlessotherwise indicated, conventional techniques of organic chemistry,pharmacology, molecular biology (including recombinant techniques), cellbiology, biochemistry, and immunology. Such techniques are explained inthe literature, such as in “Comprehensive Organic Synthesis” (B. M.Trost & I. Fleming, eds., 1991-1992); “Handbook of experimentalimmunology” (D. M. Weir & C. C. Blackwell, eds.); “Current protocols inmolecular biology” (F. M. Ausubel et al., eds., 1987, and periodicupdates); and “Current protocols in immunology” (J. E. Coligan et al.,eds., 1991), each of which is herein incorporated by reference in itsentirety.

Various aspects of the invention are set forth below in sections;however, aspects of the invention described in one particular sectionare not to be limited to any particular section. Further, when avariable is not accompanied by a definition, the previous definition ofthe variable controls.

Definitions

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names, and chemical structures may be used interchangeablyto describe the same structure. If a chemical compound is referred tousing both a chemical structure and a chemical name, and an ambiguityexists between the structure and the name, the structure predominates.These definitions apply regardless of whether a term is used by itselfor in combination with other terms, unless otherwise indicated. Hence,the definition of “alkyl” applies to “alkyl” as well as the “alkyl”portions of “hydroxyalkyl,” “fluoroalkyl,” “—O-alkyl,” etc.

The term “alkyl” is art-recognized, and includes saturated aliphaticgroups, including straight-chain alkyl groups, branched-chain alkylgroups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkylgroups, and cycloalkyl substituted alkyl groups. In certain embodiments,a straight chain or branched chain alkyl has about 30 or fewer carbonatoms in its backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ forbranched chain), and alternatively, about 20 or fewer. Likewise,cycloalkyls have from about 3 to about 10 carbon atoms in their ringstructure, and include bicycloalkyls such as where two saturatedcarbocyclic rings are fused together. In certain embodiments, thecycloalkyls have about 5, 6 or 7 carbons in the ring structure.Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, and cyclobutyl.

The term “alkylene” refers to a diradical of an alkyl group. Exemplaryalkylene groups include —CH₂CH₂—,

The term “cycloalkylene” refers to a diradical of a cycloalkyl group.Exemplary cycloalkylene groups include

The term “haloalkyl” refers to an alkyl group that is substituted withat least one halogen. Exemplary haloalkyl groups include —CH₂F, —CHF₂,—CF₃, —CH₂CF₃, —CF₂CF₃, and the like.

The term “hydroxyalkyl” refers to an alkyl group that is substitutedwith at least one hydroxyl group. Exemplary hydroxyl alkyl groupsinclude —CH₂OH, —CH₂CH₂OH, —C(H)(OH)C(OH)H₂, and the like.

The term “aralkyl” refers to an alkyl group substituted with an arylgroup. Exemplary aralkyl groups include

The term “heteroaralkyl” refers to an alkyl group substituted with aheteroaryl group.

The terms “alkenyl” and “alkynyl” are art-recognized and refer tounsaturated aliphatic groups analogous in length and possiblesubstitution to the alkyls described above, but that contain at leastone double or triple bond respectively.

The term “aryl” is art-recognized and refers to a carbocyclic aromaticgroup. Representative aryl groups include phenyl, naphthyl, anthracenyl,and the like. Unless specified otherwise, the aromatic ring may besubstituted at one or more ring positions with, for example, halogen,azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl,amino, nitro, sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl,—CO₂alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido,sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroarylmoieties, —CF₃, —CN, or the like. The term “aryl” also includespolycyclic aromatic ring systems having two or more carbocyclic rings inwhich two or more carbons are common to two adjoining rings (the ringsare “fused rings”) wherein all of the fused rings are aromatic rings,e.g., in a naphthyl group.

The term “heteroaryl” is art-recognized and refers to aromatic groupsthat include at least one ring heteroatom. In certain instances, aheteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representativeexamples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl,imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl,pyrazinyl, pyridazinyl and pyrimidinyl, and the like. Unless specifiedotherwise, the heteroaryl ring may be substituted at one or more ringpositions with, for example, halogen, azide, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino,amido, carboxylic acid, —C(O)alkyl, —CO₂alkyl, carbonyl, carboxyl,alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester,heterocyclyl, aryl or heteroaryl moieties, —CF₃, —CN, or the like. Theterm “heteroaryl” also includes polycyclic aromatic ring systems havingtwo or more rings in which two or more carbons are common to twoadjoining rings (the rings are “fused rings”) wherein all of the fusedrings are heteroaromatic, e.g., in a naphthyridinyl group.

The terms ortho, meta and para are art-recognized and refer to 1,2-,1,3- and 1,4-disubstituted benzenes, respectively. For example, thenames 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

As used herein, the terms “heterocyclic” and “heterocyclyl” represent,for example, an aromatic or nonaromatic ring (e.g., a monocyclic orbicyclic ring) containing one or more heteroatoms. The heteroatoms canbe the same or different from each other. Examples of heteratomsinclude, but are not limited to nitrogen, oxygen and sulfur. Aromaticand nonaromatic heterocyclic rings are well-known in the art. Somenonlimiting examples of aromatic heterocyclic rings include, but are notlimited to, pyridine, pyrimidine, indole, purine, quinoline andisoquinoline. Nonlimiting examples of nonaromatic heterocyclic compoundsinclude, but are not limited to, piperidine, piperazine, morpholine,pyrrolidine and pyrazolidine. Examples of oxygen containing heterocyclicrings include, but are not limited to, furan, oxirane, 2H-pyran,4H-pyran, 2H-chromene, benzofuran, and 2,3-dihydrobenzo[b][1,4]dioxine.Examples of sulfur-containing heterocyclic rings include, but are notlimited to, thiophene, benzothiophene, and parathiazine. Examples ofnitrogen containing rings include, but are not limited to, pyrrole,pyrrolidine, pyrazole, pyrazolidine, imidazole, imidazoline,imidazolidine, pyridine, piperidine, pyrazine, piperazine, pyrimidine,indole, purine, benzimidazole, quinoline, isoquinoline, triazole, andtriazine. Examples of heterocyclic rings containing two differentheteroatoms include, but are not limited to, phenothiazine, morpholine,parathiazine, oxazine, oxazole, thiazine, and thiazole. The heterocyclicring is optionally further substituted at one or more ring positionswith, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido,carboxylic acid, —C(O)alkyl, —CO₂alkyl, carbonyl, carboxyl, alkylthio,sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester,heterocyclyl, aryl or heteroaryl moieties, —CF₃, —CN, or the like. Incertain embodiments, the heterocyclyl group is a 3-7 membered ring that,unless specified otherwise, is substituted or unsubstituted.

The term “heterocycloalkyl” refers to a saturated heterocyclyl grouphaving, for example, 3-7 ring atoms.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that may berepresented by the general formulas:

wherein R⁵⁰, R⁵¹, R⁵² and R⁵³ each independently represent a hydrogen,an alkyl, an alkenyl, —(CH₂)_(m)—R⁶¹, or R⁵⁰ and R⁵¹, taken togetherwith the N atom to which they are attached complete a heterocycle havingfrom 4 to 8 atoms in the ring structure; R⁶¹ represents an aryl, acycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zeroor an integer in the range of 1 to 8. In certain embodiments, only oneof R⁵⁰ or R⁵¹ may be a carbonyl, e.g., R⁵⁰, R⁵¹ and the nitrogentogether do not form an imide. In other embodiments, R⁵⁰ and R⁵¹ (andoptionally R⁵²) each independently represent a hydrogen, an alkyl, analkenyl, or —(CH₂)_(m)—R⁶¹.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as may berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, and—O—(CH₂)_(m)—R⁶¹, where m and R⁶¹ are described above.

The term “oxo” is art-recognized and refers to a “═O” substituent. Forexample, a cyclopentane substituted with an oxo group is cyclopentanone.

The symbol “

” indicates a point of attachment.

The term “substituted” means that one or more hydrogens on the atoms ofthe designated group are replaced with a selection from the indicatedgroup, provided that the atoms' normal valencies under the existingcircumstances are not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. Theterms “stable compound” or “stable structure” refer to a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

When any substituent or variable occurs more than one time in anyconstituent or the compound of the invention, its definition on eachoccurrence is independent of its definition at every other occurrence,unless otherwise indicated.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

Certain compounds contained in compositions of the present invention mayexist in particular geometric or stereoisomeric forms. Further, certaincompounds described herein may be optically active. The presentinvention contemplates all such compounds, including cis- andtrans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers,(L)-isomers, the racemic mixtures thereof, and other mixtures thereof,as falling within the scope of the invention. The compounds may containone or more stereogenic centers. For example, asymmetric carbon atomsmay be present in a substituent such as an alkyl group. All suchisomers, as well as mixtures thereof, are intended to be included inthis invention, such as, for example, racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers.Additional asymmetric centers may be present depending upon the natureof the various substituents on the molecule. Each such asymmetric centerwill independently produce two optical isomers, and it is intended thatall of the possible optical isomers, diastereomers in mixtures, and pureor partially purified compounds are included within the ambit of thisinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers.Alternatively, a particular enantiomer of a compound of the presentinvention may be prepared by asymmetric synthesis. Still further, wherethe molecule contains a basic functional group (such as amino) or anacidic functional group (such as carboxylic acid) diastereomeric saltsare formed with an appropriate optically-active acid or base, followedby resolution of the diastereomers thus formed by fractionalcrystallization or chromatographic means known in the art, andsubsequent recovery of the pure enantiomers.

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. Chiral center(s) in a compound of the present inventioncan have the S or R configuration as defined by the IUPAC 1974Recommendations. Further, to the extent a compound described herein mayexist as a atropisomer (e.g., substituted biaryls), all forms of suchatropisomer are considered part of this invention.

As used herein, the terms “subject” and “patient” are usedinterchangeable and refer to organisms to be treated by the methods ofthe present invention. Such organisms preferably include, but are notlimited to, mammals (e.g., murines, simians, equines, bovines, porcines,canines, felines, and the like), and most preferably includes humans.

The term “IC₅₀” is art-recognized and refers to the concentration of acompound that is required for 50% inhibition of its target.

As used herein, the term “effective amount” refers to the amount of acompound sufficient to effect beneficial or desired results (e.g., atherapeutic, ameliorative, inhibitory or preventative result). Aneffective amount can be administered in one or more administrations,applications or dosages and is not intended to be limited to aparticular formulation or administration route. As used herein, the term“treating” includes any effect, e.g., lessening, reducing, modulating,ameliorating or eliminating, that results in the improvement of thecondition, disease, disorder, and the like, or ameliorating a symptomthereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as an oil/wateror water/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants. (See e.g., Martin,Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton,Pa. [1975]).

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metals (e.g.,sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate (also known astoluenesulfonate), undecanoate, and the like. Other examples of saltsinclude anions of the compounds of the present invention compounded witha suitable cation such as Na⁺, NH₄ ⁺, and NW₄ ⁺ (wherein W is a C₁₋₄alkyl group), and the like. Further examples of salts include, but arenot limited to: ascorbate, borate, nitrate, phosphate, salicylate, andsulfate. Further, acids which are generally considered suitable for theformation of pharmaceutically useful salts from basic pharmaceuticalcompounds are discussed, for example, by P. Stahl et al., Camille G.(eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.(2002) Zurich: Wiley-VCH; S. Berge et al., Journal of PharmaceuticalSciences (1977) 66 (1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference.

Additional exemplary basic salts include, but are not limited toammonium salts, alkali metal salts such as sodium, lithium, andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases (for example, organic amines)such as dicyclohexylamines, t-butyl amines, and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quarternized with agents such as lower alkyl halides (e.g.,methyl, ethyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chainhalides (e.g., decyl, lauryl, and stearyl chlorides, bromides andiodides), aralkyl halides (e.g., benzyl and phenethyl bromides), andothers.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

In addition, when a compound of the invention contains both a basicmoiety (such as, but not limited to, a pyridine or imidazole) and anacidic moiety (such as, but not limited to, a carboxylic acid)zwitterions (“inner salts”) may be formed. Such acidic and basic saltsused within the scope of the invention are pharmaceutically acceptable(i.e., non-toxic, physiologically acceptable) salts. Such salts of thecompounds of the invention may be formed, for example, by reacting acompound of the invention with an amount of acid or base, such as anequivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

The present invention includes the compounds of the invention in alltheir isolated forms (such as any solvates, hydrates, stereoisomers, andtautomers thereof). Further, the invention includes compounds in whichone or more of the atoms may be artificially enriched in a particularisotope having the same atomic number, but an atomic mass or mass numberdifferent from the atomic mass or mass number predominantly found innature. The present invention is meant to include all suitable isotopicvariations of the compounds of the invention. For example, differentisotopic forms of hydrogen (H) include protium (¹H) and deuterium (²H).Protium is the predominant hydrogen isotope found in nature. Enrichingfor deuterium may afford certain therapeutic advantages, such asincreasing in vivo half-life or reducing dosage requirements, or mayprovide a compound useful as a standard for characterization ofbiological samples. Isotopically-enriched compounds can be preparedwithout undue experimentation by conventional techniques known to thoseskilled in the art or by processes analogous to those described in theSchemes and Examples herein using appropriate isotopically-enrichedreagents and/or intermediates.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes andmethods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions ofthe present invention that consist essentially of, or consist of, therecited components, and that there are processes and methods accordingto the present invention that consist essentially of, or consist of, therecited processing steps.

The terms “a” and “an” as used herein mean “one or more” and include theplural unless the context is inappropriate.

The abbreviation “THF” is art-recognized and refers to tetrahydrofuran.The abbreviation “DCM” is art-recognized and refers to dichloromethane.The abbreviation “DMF” is art-recognized and refers todimethylformamide. The abbreviation “DMA” is art-recognized and refersto dimethylacetamide. The abbreviation “EDTA” is art-recognized andrefers to ethylenediaminetetraacetic acid. The abbreviation “TFA” isart-recognized and refers to trifluoroacetic acid.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified.

I. Tetrahydro[1,8]Naphthyridine and Related Compounds

One aspect of the invention provides a compound represented by FormulaI:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,—N(R⁴)(R⁵), —CO₂R⁶, —C(O)R⁶, —CN, —C₁₋₄alkylene-C₁₋₄alkoxy,—C₁₋₄alkylene-N(R⁴)(R⁵), —C₁₋₄alkylene-CO₂R⁶, —O—C₁₋₆alkylene-N(R⁴)(R⁵),—N(R⁴)C(O)—C₁₋₆alkylene-N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵),—N(R⁴)SO₂(C₁₋₆alkyl), —C(O)N(R⁴)(R⁵), and —N(R⁴)C(O)N(R⁴)(R⁵);

X is —O—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)-ψ, —O—C(R⁶)₂—C(R⁶)(R⁷)—C(R⁶)₂-ψ,—O—C(R⁶)₂—C(R⁶)(R⁷)—ψ, —C(R⁶)₂—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)—ψ,—C(O)—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)—ψ,—C(R⁶)₂—N(R⁸)—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)—ψ, —C(R⁶)═N—ψ, —C(R⁶)₂C(R⁶)═N—ψ,—N═C(R⁶)-ψ, or —N═C(R⁶)C(R⁶)₂—ψ; wherein ψ is a bond to the sulfonamidering nitrogen atom in Formula I;

Y is —N(R²)(R³) or —O-aralkyl, wherein said aralkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN, —CO₂—C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵), and—N(R⁴)SO₂(C₁₋₆alkyl);

R¹ represents independently for each occurrence hydrogen, halogen, orC₁₋₆alkyl;

R² is —C(O)-aryl, —C(O)-aralkyl, —C(O)—[C(R⁶)₂]_(m)-cycloalkyl,—C(O)—[C(R⁶)₂]_(m)-heterocyclyl, —C(O)—C₁₋₈alkyl,—C(O)—C₁₋₆alkylene-C₁₋₆alkoxyl, —C(O)—C₁₋₆alkylene-cycloalkyl, or—C(O)—C₁₋₆alkylene-heterocycloalkyl; each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN, —CO₂—C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵), and—N(R⁴)SO₂(C₁₋₆alkyl);

R³ is hydrogen or C₁₋₆alkyl;

R⁴ and R⁵ each represent independently for each occurrence hydrogen orC₁₋₆alkyl; or R⁴ and R⁵ taken together with the nitrogen atom to whichthey are attached form a 3-7 membered heterocyclic ring;

R⁶ represents independently for each occurrence hydrogen or C₁₋₆alkyl;

R⁷ is hydrogen, hydroxyl, C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl,—CO₂R⁶, C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or C₁₋₆alkylene-N(R⁴)(C(O)N(R⁴)(R⁵); or R⁷ isheterocycloalkyl or C₁₋₄alkylene-heterocycloalkyl, wherein theheterocycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of oxo, halogen,hydroxyl, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy;

R⁸ is hydrogen, C₁₋₆alkyl, or —C(O)—C₁₋₆alkyl;

R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkylene-N(R⁴)(R⁵), orC₁₋₆alkylene-N(R⁴)C(O)—C₁₋₆alkyl;

n is 1 or 2; and

m and p each represent independently for each occurrence 0, 1, or 2.

In certain embodiments, A is aryl or heteroaryl; each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A is aryloptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen and C₁₋₆haloalkyl. Incertain embodiments, at least one substituent is attached at themeta-position of the phenyl ring.

In certain other embodiments, A is heteroaryl optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy.

In certain embodiments, A is heterocycloalkyl optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy. In certain embodiments, A is piperidine or pyrrolidine,each of which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy.

In certain embodiments, X is —O—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)—ψ. In certainother embodiments, X is —C(R⁶)₂—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)—ψ. In certainother embodiments, X is —C(O)—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)—ψ. In certainother embodiments, X is —C(R⁶)₂—N(R⁸)—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)—ψ. Incertain other embodiments, X is —C(R⁶)═N-ψ.

In certain embodiments, Y is —N(R²)(R³). In certain embodiments, Y is—O-aralkyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl,—SO₂N(R⁴)(R⁵), and —N(R⁴)SO₂(C₁₋₆alkyl). In certain other embodiments, Yis —O-aralkyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, and —C(O)—C₁₋₆alkyl. In certain other embodiments, Y is—O— benzyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,and C₁₋₆haloalkyl.

In certain embodiments, R¹ is hydrogen.

In certain embodiments, R² is —C(O)-aryl or —C(O)-aralkyl; each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, and C₁₋₆haloalkyl. In certain otherembodiments, R² is —C(O)-aryl or —C(O)-aralkyl; each of which issubstituted with 2 substituents independently selected from the groupconsisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl,and C₁₋₆haloalkyl, and said substituents are located at theortho-positions of the aromatic ring. In certain other embodiments, R²is —C(O)-phenyl or —C(O)-benzyl; each of which is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl,and C₁₋₆haloalkyl. In certain other embodiments, R² is —C(O)-phenyl or—C(O)-benzyl; each of which is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, and C₁₋₆haloalkyl. In certain other embodiments, R²is represented by:

wherein each R′ is independently halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, or C₁₋₆haloalkyl. In certain otherembodiments, R² is represented by:

wherein each R′ is independently halogen, C₁₋₆alkyl, or C₁₋₆haloalkyl.

In certain other embodiments, R² is represented by:

wherein R″ is C₁₋₆alkyl, aryl, or heterocyclyl, each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl,—SO₂N(R⁴)(R⁵), and —N(R⁴)SO₂(C₁₋₆alkyl). In certain embodiments, R″ isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, andC₁₋₆haloalkyl.

In certain embodiments, R³ is hydrogen.

In certain embodiments, R⁷ is hydrogen. In certain other embodiments, R⁷is hydroxyl, C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl, —CO₂R⁶,C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or —N(R⁴)C(O)R⁹. In certain other embodiments, R⁷is C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆alkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), or C₁₋₆alkylene-N(R⁴)C(O)R⁹. In certain otherembodiments, R⁷ is C₁₋₃hydroxyalkyl, methyl, ethyl, orC₁₋₃alkylene-N(H)C(O)—C₁₋₄alkyl.

In certain other embodiments, R⁷ is heterocycloalkyl orC₁₋₄alkylene-heterocycloalkyl, wherein the heterocycloalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of oxo, halogen, hydroxyl, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy.

Another aspect of the invention provides a compound represented byFormula I-A:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,—N(R⁴)(R⁵), —CO₂R⁶, —C(O)R⁶, —CN, —C₁₋₄alkylene-C₁₋₄alkoxy,—C₁₋₄alkylene-N(R⁴)(R⁵), —C₁₋₄alkylene-CO₂R⁶, —O—C₁₋₆alkylene-N(R⁴)(R⁵),—N(R⁴)C(O)—C₁₋₆alkylene-N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵),—N(R⁴)SO₂(C₁₋₆alkyl), —C(O)N(R⁴)(R⁵), and —N(R⁴)C(O)N(R⁴)(R⁵);

X is —O—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)-ψ, —O—C(R⁶)₂—C(R⁶)(R⁷)—C(R⁶)₂-ψ,—O—C(R⁶)₂—C(R⁶)(R⁷)-ψ, —C(R⁶)₂—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)-ψ,—C(O)—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)-ψ,—C(R⁶)₂—N(R⁸)—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)-ψ, —C(R⁶)═N-ψ, —C(R⁶)₂C(R⁶)═N-ψ,—N═C(R⁶)-ψ, or —N═C(R⁶)C(R⁶)₂—ψ; wherein ψ is a bond to the sulfonamidering nitrogen atom in Formula I-A;

Y is —N(R²)(R³) or —O-aralkyl, wherein said aralkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN, —CO₂—C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵), and—N(R⁴)SO₂(C₁₋₆alkyl);

R¹ is hydrogen, halogen, or C₁₋₆alkyl;

R² is —C(O)-aryl, —C(O)-aralkyl, —C(O)—[C(R⁶)₂]_(m)-cycloalkyl,—C(O)—[C(R⁶)₂]_(m)-heterocyclyl, —C(O)—C₁₋₈alkyl,—C(O)—C₁₋₆alkylene-C₁₋₆alkoxyl, —C(O)—C₁₋₆alkylene-cycloalkyl, or—C(O)—C₁₋₆alkylene-heterocycloalkyl; each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN, —CO₂—C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵), and—N(R⁴)SO₂(C₁₋₆alkyl);

R³ is hydrogen or C₁₋₆alkyl;

R⁴ and R⁵ each represent independently for each occurrence hydrogen orC₁₋₆alkyl; or R⁴ and R⁵ taken together with the nitrogen atom to whichthey are attached form a 3-7 membered heterocyclic ring;

R⁶ represents independently for each occurrence hydrogen or C₁₋₆alkyl;

R⁷ is hydrogen, hydroxyl, C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl,—CO₂R⁶, C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or C₁₋₆alkylene-N(R⁴)(C(O)N(R⁴)(R⁵); or R⁷ isheterocycloalkyl or C₁₋₄alkylene-heterocycloalkyl, wherein theheterocycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of oxo, halogen,hydroxyl, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy;

R⁸ is hydrogen, C₁₋₆alkyl, or —C(O)—C₁₋₆alkyl;

R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkylene-N(R⁴)(R⁵), orC₁₋₆alkylene-N(R⁴)C(O)—C₁₋₆alkyl; and

m and p each represent independently for each occurrence 0, 1, or 2.

The definitions of variables in Formulae I-A above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionof a variable is a collection of two or more of the chemical groupsselected from those set forth above, and iii) the compound is defined bya combination of variables in which the variables are defined by (i) or(ii), e.g., such as where A is aryl, and R² is —C(O)-aryl. Further, thedefinitions of variables A, X, Y, R¹ to R⁹, m, and p described in thepreceding paragraphs in connection with Formula I are reiterated herefor use in association with Formula I-A.

Another aspect of the invention provides a compound represented byFormula II:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,—N(R⁴)(R⁵), —CO₂R⁶, —C(O)R⁶, —CN, —C₁₋₄alkylene-C₁₋₄alkoxy, and—C₁₋₄alkylene-N(R⁴)(R⁵);

Y is —N(R²)(R³) or —O-aralkyl, wherein said aralkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN, —CO₂—C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵), and—N(R⁴)SO₂(C₁₋₆alkyl);

R¹ is hydrogen, halogen, or C₁₋₆alkyl;

R² is —C(O)-aryl, —C(O)-aralkyl, —C(O)—[C(R⁶)₂]_(m)-cycloalkyl,—C(O)—[C(R⁶)₂]_(m)-heterocyclyl, —C(O)—C₁₋₈alkyl,—C(O)—C₁₋₆alkylene-C₁₋₆alkoxyl, —C(O)—C₁₋₆alkylene-cycloalkyl, or—C(O)—C₁₋₆alkylene-heterocycloalkyl; each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN, —CO₂—C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵), and—N(R⁴)SO₂(C₁₋₆alkyl);

R³ is hydrogen or C₁₋₆alkyl;

R⁴ and R⁵ each represent independently for each occurrence hydrogen orC₁₋₆alkyl; or R⁴ and R⁵ taken together with the nitrogen atom to whichthey are attached form a 3-7 membered heterocyclic ring;

R⁶ represents independently for each occurrence hydrogen or C₁₋₆alkyl;

R² is hydrogen, hydroxyl, C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl,—CO₂R⁶, C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or C₁₋₆alkylene-N(R⁴)(C(O)N(R⁴)(R⁵); or R² isheterocycloalkyl or C₁₋₄alkylene-heterocycloalkyl, wherein theheterocycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of oxo, halogen,hydroxyl, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy;

R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkylene-N(R⁴)(R⁵), orC₁₋₆alkylene-N(R⁴)C(O)—C₁₋₆alkyl; and

m and p each represent independently for each occurrence 0, 1, or 2.

In certain embodiments, A is aryl or heteroaryl; each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A is aryloptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen and C₁₋₆haloalkyl. Incertain embodiments, at least one substituent is attached at themeta-position of the phenyl ring.

In certain other embodiments, A is heterocycloalkyl optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy. In certain embodiments, A is piperidine or pyrrolidine,each of which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy.

In certain embodiments, Y is —N(R²)(R³). In certain embodiments, Y is—O-aralkyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl,—SO₂N(R⁴)(R⁵), and —N(R⁴)SO₂(C₁₋₆alkyl). In certain other embodiments, Yis —O-aralkyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, and —C(O)—C₁₋₆alkyl. In certain other embodiments, Y is—O— benzyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,and C₁₋₆haloalkyl.

In certain embodiments, R¹ is hydrogen.

In certain embodiments, R² is —C(O)-aryl or —C(O)-aralkyl; each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, and C₁₋₆haloalkyl. In certain otherembodiments, R² is —C(O)-aryl or —C(O)-aralkyl; each of which issubstituted with 2 substituents independently selected from the groupconsisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl,and C₁₋₆haloalkyl, and said substituents are located at theortho-positions of the aromatic ring. In certain other embodiments, R²is —C(O)-phenyl or —C(O)-benzyl; each of which is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl,and C₁₋₆haloalkyl. In certain other embodiments, R² is —C(O)-phenyl or—C(O)-benzyl; each of which is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, and C₁₋₆haloalkyl. In certain other embodiments, R²is represented by:

wherein each R′ is independently halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, or C₁₋₆haloalkyl. In certain otherembodiments, R² is represented by:

wherein each R′ is independently halogen, C₁₋₆alkyl, or C₁₋₆haloalkyl.

In certain embodiments, R² is represented by:

wherein R″ is C₁₋₆alkyl, aryl, or heterocyclyl, each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl,—SO₂N(R⁴)(R⁵), and —N(R⁴)SO₂(C₁₋₆alkyl). In certain embodiments, R″ isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, andC₁₋₆haloalkyl.

In certain embodiments, R³ is hydrogen.

In certain embodiments, R⁷ is hydrogen. In certain other embodiments, R⁷is hydroxyl, C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl, —CO₂R⁶,C₁₋₆alkylene-CO₂R⁶, C₁₋4hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or —N(R⁴)C(O)R⁹. In certain other embodiments, R⁷is C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆alkylene-CO₂R⁶,C₁₋₆alkylene-N(R⁴)(R⁵), or C₁₋₆alkylene-N(R⁴)C(O)R⁹. In certain otherembodiments, R⁷ is C₁₋₃hydroxyalkyl, methyl, ethyl, orC₁₋₃alkylene-N(H)C(O)—C₁₋₄alkyl.

Another aspect of the invention provides a compound represented byFormula II-A:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

A is aryl, heteroaryl, or heterocycloalkyl; each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy;

R¹ is hydrogen;

R² is —C(O)-phenyl substituted with 2 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, andC₁₋₆haloalkyl, wherein the substituents are located at the orthopositions of the phenyl ring;

R³ is hydrogen;

R⁴ and R⁵ each represent independently for each occurrence hydrogen orC₁₋₆alkyl; or R⁴ and R⁵ taken together with the nitrogen atom to whichthey are attached form a 3-7 membered heterocyclic ring;

R⁶ represents independently for each occurrence hydrogen or C₁₋₆alkyl;

R⁷ is hydrogen, hydroxyl, C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl,—CO₂R⁶, C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or C₁₋₆alkylene-N(R⁴)(C(O)N(R⁴)(R⁵); or R⁷ isheterocycloalkyl or C₁₋₄alkylene-heterocycloalkyl, wherein theheterocycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of oxo, halogen,hydroxyl, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy;

R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkylene-N(R⁴)(R⁵), orC₁₋₆alkylene-N(R⁴)C(O)—C₁₋₆alkyl; and

m and p each represent independently for each occurrence 0, 1, or 2.

In certain embodiments, A is aryl or heteroaryl; each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain otherembodiments, A is aryl optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy. Incertain other embodiments, A is phenyl optionally substituted with 1, 2,or 3 substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy. Incertain other embodiments, A is phenyl optionally substituted with 1, 2,or 3 substituents independently selected from the group consisting ofhalogen and C₁₋₆haloalkyl. In certain embodiments, at least onesubstituent is attached at the meta-position of the phenyl ring.

In certain other embodiments, A is heterocycloalkyl optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy. In certain embodiments, A is piperidine or pyrrolidine,each of which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy.

In certain embodiments, R² is represented by:

wherein each R′ is independently fluoro, chloro, or C₁₋₆haloalkyl.

In certain embodiments, R⁷ is hydrogen. In certain other embodiments, R⁷is C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl, —CO₂R⁶,C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or —N(R⁴)C(O)R⁹. In certain other embodiments, R²is C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆alkylene-CO₂R⁶,C₁₋₆alkylene-N(R⁴)(R⁵), or C₁₋₆alkylene-N(R⁴)C(O)R⁹. In certain otherembodiments, R² is C₁₋₃hydroxyalkyl, methyl, ethyl, orC₁₋₃alkylene-N(H)C(O)—C₁₋₄alkyl.

Another aspect of the invention provides a compound represented byFormula III:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,—N(R⁴)(R⁵), —CO₂R⁶, —C(O)R⁶, —CN, —C₁₋₄alkylene-C₁₋₄alkoxy, and—C₁₋₄alkylene-N(R⁴)(R⁵);

Y is —N(R²)(R³) or —O-aralkyl, wherein said aralkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN, —CO₂—C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵), and—N(R⁴)SO₂(C₁₋₆alkyl);

R¹ is hydrogen, halogen, or C₁₋₆alkyl;

R² is —C(O)-aryl, —C(O)-aralkyl, —C(O)—[C(R⁶)₂]_(m)-cycloalkyl,—C(O)—[C(R⁶)₂]_(m)-heterocyclyl, —C(O)—C₁₋₈alkyl,—C(O)—C₁₋₆alkylene-C₁₋₆alkoxyl, —C(O)—C₁₋₆alkylene-cycloalkyl, or—C(O)—C₁₋₆alkylene-heterocycloalkyl; each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN, —CO₂—C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵), and—N(R⁴)SO₂(C₁₋₆alkyl);

R³ is hydrogen or C₁₋₆alkyl;

R⁴ and R⁵ each represent independently for each occurrence hydrogen orC₁₋₆alkyl; or R⁴ and R⁵ taken together with the nitrogen atom to whichthey are attached form a 3-7 membered heterocyclic ring;

R⁶ represents independently for each occurrence hydrogen or C₁₋₆alkyl;

R⁷ is hydrogen, hydroxyl, C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl,—CO₂R⁶, C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or C₁₋₆alkylene-N(R⁴)(C(O)N(R⁴)(R⁵); or R⁷ isheterocycloalkyl or C₁₋₄alkylene-heterocycloalkyl, wherein theheterocycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of oxo, halogen,hydroxyl, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy;

R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkylene-N(R⁴)(R⁵), orC₁₋₆alkylene-N(R⁴)C(O)—C₁₋₆alkyl; and

m and p each represent independently for each occurrence 0, 1, or 2.

In certain embodiments, A is aryl or heteroaryl; each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A is aryloptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen and C₁₋₆haloalkyl. Incertain embodiments, at least one substituent is attached at themeta-position of the phenyl ring.

In certain other embodiments, A is heterocycloalkyl optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy. In certain embodiments, A is piperidine or pyrrolidine,each of which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy.

In certain embodiments, Y is —N(R²)(R³). In certain embodiments, Y is—O-aralkyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl,—SO₂N(R⁴)(R⁵), and —N(R⁴)SO₂(C₁₋₆alkyl). In certain other embodiments, Yis —O-aralkyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, and —C(O)—C₁₋₆alkyl. In certain other embodiments, Y is—O— benzyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,and C₁₋₆haloalkyl.

In certain embodiments, R¹ is hydrogen.

In certain embodiments, R² is —C(O)-aryl or —C(O)-aralkyl; each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, and C₁₋₆haloalkyl. In certain otherembodiments, R² is —C(O)-aryl or —C(O)-aralkyl; each of which issubstituted with 2 substituents independently selected from the groupconsisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl,and C₁₋₆haloalkyl, and said substituents are located at theortho-positions of the aromatic ring. In certain other embodiments, R²is —C(O)-phenyl or —C(O)-benzyl; each of which is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl,and C₁₋₆haloalkyl. In certain other embodiments, R² is —C(O)-phenyl or—C(O)-benzyl; each of which is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, and C₁₋₆haloalkyl. In certain other embodiments, R²is represented by:

wherein each R′ is independently halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, or C₁₋₆haloalkyl. In certain otherembodiments, R² is represented by:

wherein each R′ is independently halogen, C₁₋₆alkyl, or C₁₋₆haloalkyl.

In certain embodiments, R² is represented by:

wherein R″ is C₁₋₆alkyl, aryl, or heterocyclyl, each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl,—SO₂N(R⁴)(R⁵), and —N(R⁴)SO₂(C₁₋₆alkyl). In certain embodiments, R″ isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, andC₁₋₆haloalkyl.

In certain embodiments, R³ is hydrogen.

In certain embodiments, R⁷ is hydrogen. In certain other embodiments R⁷is hydroxyl, C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl, —CO₂R⁶,C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or —N(R⁴)C(O)R⁹. In certain other embodiments, R⁷is C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆alkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), or C₁₋₆alkylene-N(R⁴)C(O)R⁹. In certain otherembodiments, R⁷ is C₁₋₃hydroxyalkyl, methyl, ethyl, orC₁₋₃alkylene-N(H)C(O)—C₁₋₄alkyl.

Another aspect of the invention provides a compound represented byFormula III-A:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

A is aryl, heteroaryl, or heterocycloalkyl; each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy;

R¹ is hydrogen;

R² is —C(O)-phenyl substituted with 2 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, andC₁₋₆haloalkyl, wherein the substituents are located at the orthopositions of the phenyl ring;

R³ is hydrogen;

R⁴ and R⁵ each represent independently for each occurrence hydrogen orC₁₋₆alkyl; or R⁴ and R⁵ taken together with the nitrogen atom to whichthey are attached form a 3-7 membered heterocyclic ring;

R⁶ represents independently for each occurrence hydrogen or C₁₋₆alkyl;

R⁷ is hydrogen, hydroxyl, C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl,—CO₂R⁶, C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or C₁₋₆alkylene-N(R⁴)(C(O)N(R⁴)(R⁵); or R⁷ isheterocycloalkyl or C₁₋₄alkylene-heterocycloalkyl, wherein theheterocycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of oxo, halogen,hydroxyl, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy;

R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkylene-N(R⁴)(R⁵), orC₁₋₆alkylene-N(R⁴)C(O)—C₁₋₆alkyl; and

m and p each represent independently for each occurrence 0, 1, or 2.

In certain embodiments, A is aryl or heteroaryl; each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain otherembodiments, A is aryl optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy. Incertain other embodiments, A is phenyl optionally substituted with 1, 2,or 3 substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy. Incertain other embodiments, A is phenyl optionally substituted with 1, 2,or 3 substituents independently selected from the group consisting ofhalogen and C₁₋₆haloalkyl. In certain embodiments, at least onesubstituent is attached at the meta-position of the phenyl ring.

In certain other embodiments, A is heterocycloalkyl optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy. In certain embodiments, A is piperidine or pyrrolidine,each of which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy.

In certain embodiments, R² is represented by:

wherein each R′ is independently fluoro, chloro, or C₁₋₆haloalkyl.

In certain embodiments, R⁷ is hydrogen. In certain other embodiments, R⁷is C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl, —CO₂R⁶,C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or —N(R⁴)C(O)R⁹. In certain other embodiments, R⁷is C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆alkylene-CO₂R⁶,C₁₋₆alkylene-N(R⁴)(R⁵), or C₁₋₆alkylene-N(R⁴)C(O)R⁹. In certain otherembodiments, R⁷ is C₁₋₃hydroxyalkyl, methyl, ethyl, orC₁₋₃alkylene-N(H)C(O)—C₁₋₄alkyl.

Another aspect of the invention provides a compound represented byFormula IV:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,—N(R⁴)(R⁵), —CO₂R⁶, —C(O)R⁶, —CN, —C₁₋₄alkylene-C₁₋₄alkoxy, and—C₁₋₄alkylene-N(R⁴)(R⁵);

Y is —N(R²)(R³) or —O-aralkyl, wherein said aralkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN, —CO₂—C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵), and—N(R⁴)SO₂(C₁₋₆alkyl);

R¹ is hydrogen, halogen, or C₁₋₆alkyl;

R² is —C(O)-aryl, —C(O)-aralkyl, —C(O)—[C(R⁶)₂]_(m)-cycloalkyl,—C(O)—[C(R⁶)₂]_(m)-heterocyclyl, —C(O)—C₁₋₈alkyl,—C(O)—C₁₋₆alkylene-C₁₋₆alkoxyl, —C(O)—C₁₋₆alkylene-cycloalkyl, or—C(O)—C₁₋₆alkylene-heterocycloalkyl; each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy,C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN, —CO₂—C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵), and—N(R⁴)SO₂(C₁₋₆alkyl);

R³ is hydrogen or C₁₋₆alkyl;

R⁴ and R⁵ each represent independently for each occurrence hydrogen orC₁₋₆alkyl; or R⁴ and R⁵ taken together with the nitrogen atom to whichthey are attached form a 3-7 membered heterocyclic ring;

R⁶ represents independently for each occurrence hydrogen or C₁₋₆alkyl;

R⁷ is hydrogen, hydroxyl, C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl,—CO₂R⁶, C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or C₁₋₆alkylene-N(R⁴)(C(O)N(R⁴)(R⁵); or R⁷ isheterocycloalkyl or C₁₋₄alkylene-heterocycloalkyl, wherein theheterocycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of oxo, halogen,hydroxyl, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy;

R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkylene-N(R⁴)(R⁵), orC₁₋₆alkylene-N(R⁴)C(O)—C₁₋₆alkyl; and

m and p each represent independently for each occurrence 0, 1, or 2.

In certain embodiments, A is aryl or heteroaryl; each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A is aryloptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen and C₁₋₆haloalkyl. Incertain embodiments, at least one substituent is attached at themeta-position of the phenyl ring.

In certain other embodiments, A is heterocycloalkyl optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy. In certain embodiments, A is piperidine or pyrrolidine,each of which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy.

In certain embodiments, Y is —N(R²)(R³). In certain embodiments, Y is—O-aralkyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl,—SO₂N(R⁴)(R⁵), and —N(R⁴)SO₂(C₁₋₆alkyl). In certain other embodiments, Yis —O-aralkyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, and —C(O)—C₁₋₆alkyl. In certain other embodiments, Y is—O— benzyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,and C₁₋₆haloalkyl.

In certain embodiments, R¹ is hydrogen.

In certain embodiments, R² is —C(O)-aryl or —C(O)-aralkyl; each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, and C₁₋₆haloalkyl. In certain otherembodiments, R² is —C(O)-aryl or —C(O)-aralkyl; each of which issubstituted with 2 substituents independently selected from the groupconsisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl,and C₁₋₆haloalkyl, and said substituents are located at theortho-positions of the aromatic ring. In certain other embodiments, R²is —C(O)-phenyl or —C(O)-benzyl; each of which is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl,and C₁₋₆haloalkyl. In certain other embodiments, R² is —C(O)-phenyl or—C(O)-benzyl; each of which is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, and C₁₋₆haloalkyl. In certain other embodiments, R²is represented by:

wherein each R′ is independently halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, or C₁₋₆haloalkyl. In certain otherembodiments, R² is represented by:

wherein each R′ is independently halogen, C₁₋₆alkyl, or C₁₋₆haloalkyl.

In certain embodiments, R² is represented by:

wherein R″ is C₁₋₆alkyl, aryl, or heterocyclyl, each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl,—SO₂N(R⁴)(R⁵), and —N(R⁴)SO₂(C₁₋₆alkyl). In certain embodiments, R″ isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, andC₁₋₆haloalkyl.

In certain embodiments, R³ is hydrogen.

In certain embodiments, R⁷ is hydrogen. In certain other embodiments R⁷is hydroxyl, C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl, —CO₂R⁶,C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or —N(R⁴)C(O)R⁹. In certain other embodiments, R⁷is C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆alkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), or C₁₋₆alkylene-N(R⁴)C(O)R⁹. In certain otherembodiments, R⁷ is C₁₋₃hydroxyalkyl, methyl, ethyl, orC₁₋₃alkylene-N(H)C(O)—C₁₋₄alkyl.

Another aspect of the invention provides a compound of Formula V:

or a pharmaceutically acceptable salt or solvate thereof; wherein:

A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,—N(R⁴)(R⁵), —CO₂R⁶, —C(O)R⁶, —CN, —C₁₋₄alkylene-C₁₋₄alkoxy, and—C₁₋₄alkylene-N(R⁴)(R⁵);

Y is —N(R²)(R³) or —O-aralkyl, wherein said aralkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN, —CO₂—C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵), and—N(R⁴)SO₂(C₁₋₆alkyl);

R¹ is hydrogen, halogen, or C₁₋₆alkyl;

R² is —C(O)-aryl, —C(O)-aralkyl, —C(O)—[C(R⁶)₂]_(m)-cycloalkyl,—C(O)—[C(R⁶)₂]_(m)-heterocyclyl, —C(O)—C₁₋₈alkyl,—C(O)—C₁₋₆alkylene-C₁₋₆alkoxyl, —C(O)—C₁₋₆alkylene-cycloalkyl, or—C(O)—C₁₋₆alkylene-heterocycloalkyl; each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN, —CO₂—C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵), and—N(R⁴)SO₂(C₁₋₆alkyl);

R³ is hydrogen or C₁₋₆alkyl;

R⁴ and R⁵ each represent independently for each occurrence hydrogen orC₁₋₆alkyl; or R⁴ and R⁵ taken together with the nitrogen atom to whichthey are attached form a 3-7 membered heterocyclic ring;

R⁶ represents independently for each occurrence hydrogen or C₁₋₆alkyl;and

m and p each represent independently for each occurrence 0, 1, or 2.

In certain embodiments, A is aryl or heteroaryl; each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A is aryloptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy. In certain other embodiments, A isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen and C₁₋₆haloalkyl. Incertain embodiments, at least one substituent is attached at themeta-position of the phenyl ring.

In certain other embodiments, A is heterocycloalkyl optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy. In certain embodiments, A is piperidine or pyrrolidine,each of which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy.

In certain embodiments, Y is —N(R²)(R³). In certain embodiments, Y is—O-aralkyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl,—SO₂N(R⁴)(R⁵), and —N(R⁴)SO₂(C₁₋₆alkyl). In certain other embodiments, Yis —O-aralkyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, and —C(O)—C₁₋₆alkyl. In certain other embodiments, Y is—O— benzyl optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁₋₆alkyl,and C₁₋₆haloalkyl.

In certain embodiments, R¹ is hydrogen.

In certain embodiments, R² is —C(O)-aryl or —C(O)-aralkyl; each of whichis optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, and C₁₋₆haloalkyl. In certain otherembodiments, R² is —C(O)-aryl or —C(O)-aralkyl; each of which issubstituted with 2 substituents independently selected from the groupconsisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl,and C₁₋₆haloalkyl, and said substituents are located at theortho-positions of the aromatic ring. In certain other embodiments, R²is —C(O)-phenyl or —C(O)-benzyl; each of which is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl,and C₁₋₆haloalkyl. In certain other embodiments, R² is —C(O)-phenyl or—C(O)-benzyl; each of which is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, and C₁₋₆haloalkyl. In certain other embodiments, R²is represented by:

wherein each R′ is independently halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, or C₁₋₆haloalkyl. In certain otherembodiments, R² is represented by:

wherein each R′ is independently halogen, C₁₋₆alkyl, or C₁₋₆haloalkyl.

In certain embodiments, R² is represented by:

wherein R″ is C₁₋₆alkyl, aryl, or heterocyclyl, each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl,—SO₂N(R⁴)(R⁵), and —N(R⁴)SO₂(C₁₋₆alkyl). In certain embodiments, R″ isphenyl optionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, andC₁₋₆haloalkyl.

In certain embodiments, R³ is hydrogen.

In certain embodiments, R⁷ is hydrogen. In certain other embodiments R⁷is hydroxyl, C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl, —CO₂R⁶,C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or —N(R⁴)C(O)R⁹. In certain other embodiments, R⁷is C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆alkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), or C₁₋₆alkylene-N(R⁴)C(O)R⁹. In certain otherembodiments, R⁷ is C₁₋₃hydroxyalkyl, methyl, ethyl, orC₁₋₃alkylene-N(H)C(O)—C₁₋₄alkyl.

The definitions of variables in Formulae I through V above encompassmultiple chemical groups. The application contemplates embodimentswhere, for example, i) the definition of a variable is a single chemicalgroup selected from those chemical groups set forth above, ii) thedefinition is a collection of two or more of the chemical groupsselected from those set forth above, and iii) the compound is defined bya combination of variables in which the variables are defined by (i) or(ii).

In certain other embodiments, the compound is one of the compoundslisted in Tables 1-3 below or a pharmaceutically acceptable salt thereof

TABLE 1

No. Y Z I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

TABLE 2

        No.         Y

        Z II-1

II-2

II-3

II-4

II-5

II-6

II-7

II-8

II-9

II-10

II-11

II-12

II-13

II-14

II-15

II-16

II-17

II-18

II-19

II-20

II-21

II-22

II-23

II-24

II-25

II-26

II-27

II-28

II-29

II-30

II-31

II-32

II-33

II-34

II-35

TABLE 3 No. Compound III-1

III-2

III-3

III-4

III-5

III-6

III-7

III-8

III-9

III-10

III-11

III-12

III-13

III-14

III-15

III-16

III-17

III-18

III-19

III-20

III-21

III-22

III-23

III-24

III-25

III-26

III-27

III-28

III-29

III-30

III-31

III-32

III-33

III-34

III-35

III-36

III-37

III-38

III-39

III-40

III-41

III-42

III-43

III-44

III-45

III-46

III-47

III-48

III-49

III-50

III-51

III-52

Methods for preparing compounds described herein are illustrated in thefollowing synthetic schemes. The schemes are given for the purpose ofillustrating the invention, and are not intended to limit the scope orspirit of the invention. Starting materials shown in the schemes can beobtained from commercial sources or be prepared based on proceduresdescribed in the literature.

The synthetic route illustrated in Scheme 1 is a general method forpreparing amide-substituted 5,6,7,8-tetrahydro[1,8]naphthyridinecompounds. Reaction of diaminopyridine A with a mixture of an acid andsubstituted dimethylaminoacrolein B provides amino-1,8-naphthyridine C.Alternatively, amino-1,8-naphthyridine C can be prepared by reactingdiaminopyridine A with 1,3-dicarbonyl compound B1 (See, for example,Reichart et al. in Tet. Lett. 1977, 24, 2087-90; Eva, E. et al. J. Het.Chem. 1976, 13, 841-844, and Bernstein et al. J. Amer. Chem. Soc. 1947,69, 1151-1158) or substituted vinamidinium salt B2 (See, for example,Norma et al. in Synthesis 2001, 9, 1351-1355).

Reaction of amino-1,8-naphthyridine C with an acylating reagent (e.g.,an acid chloride) provides amido-1,8-naphthyridine D. Reduction ofamido-1,8-naphthyridine D by hydrogenation providesamido-tetrahydro-1,8-naphthyridine E, which can be reacted with asulphonyl chloride or sulfamoyl chloride to provide the finalsulfonamide-tetrahydro-1,8-naphthyridine F.

The reaction procedures in Scheme 1 are contemplated to be amenable topreparing a wide variety of amide-substitutedtetrahydro[1,8]naphthyridine compounds having different substituents atthe R through R^(V) positions. For example, numerous substituted2,6-diaminopyridines are known in the literature and/or are commerciallyavailable. Furthermore, if a functional group that is part of theR—R^(V) group would not be amenable to a reaction condition described inScheme 1, it is contemplated that the functional group can first beprotected using standard protecting group chemistry and strategies, andthen the protecting group is removed after completing the desiredsynthetic transformation. See, for example, Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991, for further description of protecting chemistry and strategies. Incertain other embodiments, a functional group in substituent R throughR^(V) in tetrahydro[1,8]naphthyridine F can converted to anotherfunctional group using standard functional group manipulation proceduresknown in the art. See, for example, “Comprehensive Organic Synthesis”(B. M. Trost & I. Fleming, eds., 1991-1992)

Scheme 2 illustrates a general method for preparingamido-dihydro-2H-pyrido[3,2-b][1,4]oxazines. Alkylation ofnitro-hydroxy-pyridine A with a 2-haloester provides pyridinyl ether B.Conversion of nitro-hydroxy-pyridine A to pyridinyl ether B can also becarried out by Mitsunobu alkylation of a 2-hydroxyester. Next, reductivecyclization of pyridinyl ether B affords4H-pyrido[3,2-b][1,4]oxazine-3-one C. Reduction of the amide using, forexample, a hydride (e.g., a borane or lithium aluminum hydride) providesdihydro-2H-pyrido[3,2-b][1,4]oxazine D. Treatment of oxazine D with asulphonyl chloride or sulfamoyl chloride providessulfonamido-bromo-dihydro-2H-pyrido[3,2-b][1,4]oxazine E.

Bromo-dihydro-2H-pyrido[3,2-b][1,4]oxazine E can be converted toamino-dihydro-2H-pyrido[3,2-b][1,4]oxazine F using procedures known inthe art, such as (1) Ullmann CuSO₄ mediated addition of ammonia (Hauseret al. in J. Org. Chem. 1950, 15, 1224-1232); (2) Pd-mediated additionof a carbamate (Bhagwanth et al. in J. Org Chem. 2009, 74, 4634-4637)followed by deprotection; (3) Pd-mediated addition ofhexamethyldisilazide (Stefko et al. in J. Org. Chem. 2011, 76,6619-6635), and (4) Pd-mediated addition of diphenylmethanimine followedby deprotection with acid (Grasa et al. in J. Org. Chem. 2001, 66,7729-7737). Reaction of amine F with an acid chloride provides amide G.It is understood that an acid (R^(I)CO₂H) and amide-coupling reagent canbe used in lieu of the acid chloride in the step used to produce amideG.

Reacting halo-amino-pyridine A with a Negishi reagent (formed from a2-((tert-butoxycarbonyl)amino)-3-iodopropanoate) provides amino acid B.Then, intramolecular cyclization of amino acid B promoted by heat or abase provides dihydro-1,8-naphthyridin-2(1H)-one C. Reactingdihydro-1,8-naphthyridin-2(1H)-one C with benzylchloroformate affordsbis-carbamate D. Selective reduction of the amide group in bis-carbamateD using borane or lithium aluminum hydride providestetrahydro-1,8-naphthyridine E. Reaction of tetrahydro-1,8-naphthyridineE with a sulphonyl chloride or sulfamoyl chloride provides sulfonamideF. Next, the benzylcarbamate protecting group is removed fromsulfonamide F to provide an amino-tetrahydro-1,8-naphthyridine (notshown) that can be subjected to amide coupling conditions using acarboxylic acid and an amide coupling agent to provideamido-tetrahydro-1, 8-naphthyridine G. The remaining Boc protectinggroup on amido-tetrahydro-1,8-naphthyridine G can be removed bytreatment with acid to provide amino-tetrahydro-1,8-naphthyridine H. Itis understood that the amino group on amino-tetrahydro-1,5-naphthyridineH can be converted to other functional groups (e.g., by reaction with analkylating agent(s), aldehyde (reductive alkylations), acyl halide,sulphonyl chloride, isocyanate, and the like) to afford the compound I.

Scheme 4 illustrates an alternative general method for preparingamido-dihydro-2H-pyrido[3,2-b][1,4]oxazines. Alkylation ofhydroxy-pyridine A with 2-halo-alkanone B affords pyridinyl ether C.Exhaustive reduction (e.g., using Raney Nickel) with in situintramolecular cyclization providesbromo-dihydro-2H-pyrido[3,2-b]oxazine D. Reaction of oxazine D with asulphonyl chloride or sulfamoyl chloride providesbromo-sulfonamido-dihydro-2H-pyrido[3,2-b]oxazine E.Bromo-sulfonamido-dihydro-2H-pyrido[3,2-b]oxazine E can be converted toamine F using procedures known in the art, such as (1) Ullmann CuSO₄mediated addition of ammonia (Hauser et al. in J. Org. Chem. 1950, 15,1224-1232); (2) Pd-mediated addition of a carbamate (Bhagwanth et al. inJ. Org Chem. 2009, 74, 4634-4637) followed by deprotection; (3)Pd-mediated addition of hexamethyldisilazide (Stefko et al. in J. Org.Chem. 2011, 76, 6619-6635), and (4) Pd-mediated addition ofdiphenylmethanimine followed by deprotection with acid (Grasa et al. inJ. Org. Chem. 2001, 66, 7729-7737). Reaction of amine F with an acidchloride provides amide G. It is understood that an acid (R^(I)CO₂H) andamide-coupling reagent can be used in lieu of the acid chloride in thestep used to produce amide G.

Scheme 5 illustrates another general procedure for preparingamido-tetrahydro-1,8-naphthyridines with a hydroxyl or alkoxyl group atthe 6-position. Reacting halo-amino-pyridine A with a Negishi reagent(formed from a 2-alkoxy-3-iodopropanoate) provides pyridinyl ester B.Then, intramolecular cyclization of pyridinyl ester B promoted by heator a base provides dihydro-1,8-naphthyridin-2(1H)-one C. Reactingdihydro-1,8-naphthyridin-2(1H)-one C with benzylchloroformate affordsbis-carbamate D. Selective reduction of the amide group in bis-carbamateD using borane or lithium aluminum hydride providestetrahydro-1,8-naphthyridine E. Reaction of tetrahydro-1,8-naphthyridineE with a sulphonyl chloride or sulfamoyl chloride provides sulfonamideF. Next, the benzylcarbamate protecting group is removed fromsulfonamide F to provide an amino-tetrahydro-1,8-naphthyridine (notshown) that can be subjected to amide coupling conditions using acarboxylic acid and an amide coupling agent to provideamido-tetrahydro-1,8-naphthyridine G. To the extent ahydroxy-tetrahydro-1,8-naphthyridine is desired, variable R^(IV) may bea trialkylsilyl group, which may be removed by reactingamido-tetrahydro-1,8-naphthyridine G with a silyl group deprotectingagent, such as tetrabutylammonium fluoride.

Scheme 6 illustrates another general procedure for preparingaralkyloxy-tetrahydro-1,8-naphthyridine compounds. Reaction ofaralkyloxy-aminopyridine A with a mixture of an acid and substituteddimethylaminoacrolein B provides 1,8-naphthyridine C. Alternatively,1,8-naphthyridine C can be prepared by reacting aralkyloxy-aminopyridinewith 1,3-dicarbonyl compound B1 (See, for example, Reichart et al. inTet. Lett. 1977, 24, 2087-90; Eva, E. et al. J. Het. Chem. 1976, 13,841-844, and Bernstein et al. J. Amer. Chem. Soc. 1947, 69, 1151-1158)or substituted vinamidinium salt B2 (See, for example, Norma et al. inSynthesis 2001, 9, 1351-1355). Reduction of 1,8-naphthyridine C byhydrogenation (e.g., using H₂ with Pd/C in methanol) providestetrahydro-1,8-naphthyridine D, which can be reacted with a sulphonylchloride or sulfamoyl chloride to provide the finalaralkyloxy-sulfonamide-tetrahydro-1,8-naphthyridine E.

Scheme 7 illustrates an alternative general procedure for preparingaralkyloxy-dihydro-2H-pyrido[3,2-b][1,4]oxazines. Ullman coupling of analcohol (R^(VIII)—OH) with bromide A providesaralkyloxy-dihydro-2H-pyrido[3,2-b][1,4]oxazine B.

II. Therapeutic Applications of Tetrahydro[1,8]naphthyridine and RelatedCompounds

It is contemplated that the tetrahydro[1,8]naphthyridine and relatedcompounds described herein, such as a compound of Formula I, II, III,IV, or V, provide therapeutic benefits to subjects suffering from acancer, bacterial infection, fungal infection, or immune deficiencydisorder. Accordingly, one aspect of the invention provides a method oftreating a disorder selected from the group consisting of cancer,bacterial infection, fungal infection, and immune deficiency disorder.The method comprises administering a therapeutically effective amount ofa tetrahydro[1,8]naphthyridine or related compound described herein,such as a compound of Formula I, II, III, IV, or V, to a subject in needthereof to ameliorate a symptom of the disorder, wherein Formula I, II,III, IV, and V are as described above. In certain embodiments, theparticular compound of Formula I, II, III, IV, or V is a compounddefined by one of the embodiments described above.

In certain embodiments, the disorder is cancer. In certain embodiments,the cancer is a solid tumor or leukemia. In certain other embodiments,the cancer is colon cancer, pancreatic cancer, breast cancer, ovariancancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma,adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lungcancer, leukemia, bladder cancer, stomach cancer, cervical cancer,testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidneycancer, uterus cancer, espophagus cancer, liver cancer, an acousticneuroma, oligodendroglioma, meningioma, neuroblastoma, orretinoblastoma. In certain other embodiments, the cancer is small celllung cancer, non-small cell lung cancer, melanoma, cancer of the centralnervous system tissue, brain cancer, Hodgkin's lymphoma, non-Hodgkin'slymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, ordiffuse large B-Cell lymphoma. In certain other embodiments, the canceris breast cancer, colon cancer, small-cell lung cancer, non-small celllung cancer, prostate cancer, renal cancer, ovarian cancer, leukemia,melanoma, or cancer of the central nervous system tissue. In certainother embodiments, the cancer is colon cancer, small-cell lung cancer,non-small cell lung cancer, renal cancer, ovarian cancer, renal cancer,or melanoma.

Additional exemplary cancers include fibrosarcoma, myxosarcoma,liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cellcarcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma,sebaceous gland carcinoma, papillary carcinoma, papillaryadenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogeniccarcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma,choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, epithelialcarcinoma, glioma, astrocytoma, medulloblastoma, and hemangioblastoma.

In certain embodiments, the caner is a neuroblastoma, meningioma,hemangiopericytoma, multiple brain metastase, glioblastoma multiforms,glioblastoma, brain stem glioma, poor prognosis malignant brain tumor,malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma,neuroendocrine tumor, rectal adeno carcinoma, Dukes C & D colorectalcancer, unresectable colorectal carcinoma, metastatic hepatocellularcarcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia,Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma,cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low gradefollicular lymphoma, metastatic melanoma, localized melanoma, malignantmesothelioma, malignant pleural effusion mesothelioma syndrome,peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma,soft tissue sarcoma, scelroderma, cutaneous vasculitis, Langerhans cellhistiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive,hormone refractory prostate cancer, resected high-risk soft tissuesarcoma, unrescectable hepatocellular carcinoma, Waidenstrom'smacroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tubecancer, androgen independent prostate cancer, androgen dependent stageIV non-metastatic prostate cancer, hormone-insensitive prostate cancer,chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma,follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma.

In certain embodiments, the disorder is a bacterial infection. Thebacterial infection can be characterized according to classificationsknown in the art. For example, in certain embodiments, the bacterialinfection is a gram-positive bacterial infection, such as agram-positive cocci bacterial infection or a gram-positive bacillibacterial infection. In other embodiments, the bacterial infection is agram-negative bacterial infection, such as a gram-negative coccibacterial infection or a gram-negative bacilli bacterial infection. Thebacterial infection can also be characterized according to whether it iscaused by anaerobic or aerobic bacteria. Accordingly, in certainembodiments, the bacterial infection is an anaerobic bacterialinfection. In certain other embodiments, the bacterial infection is anaerobic bacterial infection.

A variety of bacteria are contemplated to be susceptible to thetetrahydro[1,8]naphthyridine compounds. Representative bacteria includeStaphylococci species, e.g., S. aureus; Enterococci species, e.g., E.faecalis and E. faecium; Streptococci species, e.g., S. pyogenes and S.pneumoniae; Escherichia species, e.g., E. coli, includingenterotoxigenic, enteropathogenic, enteroinvasive, enterohemorrhagic andenteroaggregative E. coli strains; Haemophilus species, e.g., H.influenza; and Moraxella species, e.g., M. catarrhalis. Other examplesinclude Mycobacteria species, e.g., M. tuberculosis, M.avian-intracellulare, M. kansasii, M. bovis, M. africanum, M. genavense,M leprae, M. xenopi, M simiae, M. scrofulaceum, M. malmoense, M.celatum, M. abscessus, M. chelonae, M. szulgai, M gordonae, M.haemophilum, M. fortuni and M. marinum; Corynebacteria species, e.g., C.diphtheriae; Vibrio species, e.g., V. cholerae; Campylobacter species,e.g., C. jejuni; Helicobacter species, e.g., H. pylori; Pseudomonasspecies, e.g., P. aeruginosa; Legionella species, e.g., L. pneumophila;Treponema species, e.g., T. pallidum; Borrelia species, e.g., B.burgdorferi; Listeria species, e.g., L monocytogenes; Bacillus species,e.g., B. cereus; Bordatella species, e.g., B. pertussis; Clostridiumspecies, e.g., C. perfringens, C. tetani, C. difficile and C. botulinum;Neisseria species, e.g., N. meningitidis and N. gonorrhoeae; Chlamydiaspecies, e.g., C. psittaci, C. pneumoniae and C. trachomatis; Rickettsiaspecies, e.g., R. rickettsii and R. prowazekii; Shigella species, e.g.,S. sonnei; Salmonella species, e.g., S. typhimurium; Yersinia species,e.g., Y. enterocolitica and Y. pseudotuberculosis; Klebsiella species,e.g., K pneumoniae; Mycoplasma species, e.g., M. pneumoniae; andTrypanosoma brucei. In certain embodiments, the compounds describedherein are used to treat a subject suffering from a bacterial infectionselected from the group consisting of S. aureus, E. faecalis, E.faecium, S. pyogenes, S. pneumonia, and P. aeruginosa.

The antibacterial activity of compounds described herein may beevaluated using assays known in the art, such as the microbroth dilutionminimum inhibition concentration (MIC) assay, as further described inNational Committee for Clinical Laboratory Standards. PerformanceStandards for Antimicrobial Susceptibility Testing; FourteenthInformational Supplement. NCCLS document M100-S14 {ISBN 1-56238-516-X}.This assay may be used to determine the minimum concentration of acompound necessary to prevent visible bacterial growth in a solution. Ingeneral, the drug to be tested is serially diluted into wells, andaliquots of liquid bacterial culture are added. This mixture isincubated under appropriate conditions, and then tested for growth ofthe bacteria. Compounds with low or no antibiotic activity (a high MIC)will allow growth at high concentrations of compound, while compoundswith high antibiotic activity will allow bacterial growth only at lowerconcentrations (a low MIC).

The assay uses stock bacterial culture conditions appropriate for thechosen strain of bacteria. Stock cultures from the permanent stockculture collection can be stored as frozen suspensions at −70° C.Cultures may be suspended in 10% skim milk (BD) prior to snap freezingin dry ice/ethanol and then placed in a −70° C. freezer. Cultures may bemaintained on Tryptic Soy Agar containing 5% Sheep Blood at roomtemperature (20° C.), and each culture may be recovered from frozen formand transferred an additional time before MIC testing. Fresh plates areinoculated the day before testing, incubated overnight, and checked toconfirm purity and identity.

The identity and purity of the cultures recovered from the stock culturecan be confirmed to rule out the possibility of contamination. Theidentity of the strains may be confirmed by standard microbiologicalmethods (See, e.g., Murray et al., Manual of Clinical Microbiology,Eighth Edition. ASM Press {ISBN 1-55581-255-4}). In general, culturesare streaked onto appropriate agar plates for visualization of purity,expected colony morphology, and hemolytic patterns. Gram stains can alsobe utilized. The identities are confirmed using a MicroScan WalkAway 40SI Instrument (Dade Behring, West Sacramento, Calif.). This deviceutilizes an automated incubator, reader, and computer to assess foridentification purposes the biochemical reactions carried out by eachorganism. The MicroScan WalkAway can also be used to determine apreliminary MIC, which may be confirmed using the method describedbelow.

Frozen stock cultures may be used as the initial source of organisms forperforming microbroth dilution minimum inhibition concentration (MIC)testing. Stock cultures are passed on their standard growth medium forat least 1 growth cycle (18-24 hours) prior to their use. Most bacteriamay be prepared directly from agar plates in 10 mL aliquots of theappropriate broth medium. Bacterial cultures are adjusted to the opacityof a 0.5 McFarland Standard (optical density value of 0.28-0.33 on aPerkin-Elmer Lambda EZ150 Spectrophotometer, Wellesley, Mass., set at awavelength of 600 nm). The adjusted cultures are then diluted 400 fold(0.25 mL inoculum+100 mL broth) in growth media to produce a startingsuspension of approximately 5×105 colony forming units (CFU)/mL. Mostbacterial strains may be tested in cation adjusted Mueller Hinton Broth(CAMHB).

Test compounds (“drugs”) are solubilized in a solvent suitable for theassay, such as DMSO. Drug stock solutions may be prepared on the day oftesting. Microbroth dilution stock plates may be prepared in twodilution series, 64 to 0.06 μg drug/mL and 0.25 to 0.00025 μg drug/mL.For the high concentration series, 200 μL of stock solution (2 mg/mL) isadded to duplicate rows of a 96-well microtiter plate. This is used asthe first well in the dilution series. Serial two-fold decrementaldilutions are made using a BioMek FX robot (Beckman Coulter Inc.,Fullerton, Calif.) with 10 of the remaining 11 wells, each of which willcontain 100 μL of the appropriate solvent/diluent. Row 12 containssolvent/diluent only and serves as the control. For the first well ofthe low concentration series, 200 μL of an 8 μg/mL stock are added toduplicate rows of a 96-well plate. Serial two-fold dilutions are made asdescribed above.

Daughter 96-well plates may be spotted (3.2 μL/well) from the stockplates listed above using the BioMek FX robot and used immediately orfrozen at −70° C. until use. Aerobic organisms are inoculated (100 μLvolumes) into the thawed plates using the BioMek FX robot. Theinoculated plates are be placed in stacks and covered with an emptyplate. These plates are then incubated for 16 to 24 hours in ambientatmosphere according to CLSI guidelines (National Committee for ClinicalLaboratory Standards, Methods for Dilution, Antimicrobial Tests forBacteria that Grow Aerobically; Approved Standard-Sixth Edition. NCCLSdocument M7-A6 {ISBN 1-56238-486-4}).

After inoculation and incubation, the degree of bacterial growth can beestimated visually with the aid of a Test Reading Mirror (DynexTechnologies 220 16) in a darkened room with a single light shiningdirectly through the top of the microbroth tray. The MIC is the lowestconcentration of drug that prevents macroscopically visible growth underthe conditions of the test.

In certain embodiments, the disorder is a fungal infection. Exemplaryfungi that may be treated include, for example, Acremonium, Absidia(e.g., Absidia corymbifera), Alternaria, Aspergillus (e.g., Aspergillusclavatus, Aspergillus flavus, Aspergillus fumigatus, Aspergillusnidulans, Aspergillus niger, Aspergillus terreus, and Aspergillusversicolor), Aureobasidium, Basidiobolus, Blastomyces (e.g., Blastomycesdermatitidis), Candida (e.g., Candida albicans, Candida glabrata,Candida guilliermondii, Candida kefyr, Candida krusei, Candidalusitaniae, Candida parapsilosis, Candida pseudotropicalis, Candidastellatoidea, Candida tropicalis, Candida utilis, Candida lipolytica,Candida famata and Candida rugosa), Cephalosporium, Chaetomium,Chrysosporium, Cladosporium (e.g., Cladosporium carrionii andCladosporium trichloides), Coccidioides (e.g., Coccidioides immitis),Conidiobolus, Coprinus, Corynespora, Cryptococcus (e.g., Cryptococcusneoformans), Curvularia, Cunninghamella (e.g., Cunninghamella elegans),Exophiala (e.g., Exophiala dermatitidis and Exophiala spinifera),Epidermophyton (e.g., Epidermophyton floccosum), Fonsecaea (e.g.,Fonsecaea pedrosoi), Fusarium (e.g., Fusarium solani), Geotrichum (e.g.,Geotrichum candiddum and Geotrichum clavatum), Hendersonula,Histoplasma, Leptosphaeria, Loboa, Madurella, Malassezia (e.g.,Malassezia furfur), Microsporum (e.g., Microsporum canis and Microsporumgypseum), Mycocentrospora, Mucor, Neotestudina, Paecilomyces,Paracoccidioides (e.g., Paracoccidioides brasiliensis), Penicillium(e.g., Penicillium marneffei), Phialophora, Pneumocystis (e.g.,Pneumocystis carinii), Pseudallescheria (e.g., Pseudallescheria boydii),Rhinosporidium, Rhizomucor, Rhizopus (e.g., Rhizopus microsporus var.rhizopodiformis and Rhizopus oryzae), Saccharomyces (e.g., Saccharomycescerevisiae), Scopulariopsis, Sporothrix (e.g., Sporothrix schenckii),Trichophyton (e.g., Trichophyton mentagrophytes and Trichophytonrubrum), Trichosporon (e.g., Trichosporon asahii, Trichosporon beigeliiand Trichosporon cutaneum), and Wangiella.

In certain embodiments, the disorder is an immune deficiency disorder.Exemplary immune deficiency disorders include, for example, a humanimmunodeficiency viral infection, a patient with a deficient immunesystem due to chemotherapy, or a patient recovering from surgery who hasa deficient immune system.

In certain embodiments, the subject is a human.

Another aspect of the invention provides for the use of a compounddescribed herein (such as a compound of Formula I, II, III, IV, or V) inthe manufacture of a medicament. In certain embodiments, the medicamentis for treating a disorder described herein, such as cancer.

Another aspect of the invention provides for the use of a compounddescribed herein (such as a compound of Formula I, II, III, IV, or V)for treating a medical disorder, such a medical disorder describedherein (e.g., cancer).

Further, it is contemplated that tetrahydro[1,8]naphthyridine andrelated compounds described herein, such as a compound of Formula I, II,III, IV, or V, can promote the activity of RORγ. Accordingly, anotheraspect of the invention provides a method of promoting the activity ofRORγ. The method comprises exposing a RORγ to an effective amount of atetrahydro[1,8]naphthyridine or related compound described herein, suchas a compound of Formula I, II, III, IV, or V, to promote RORγ activity,wherein Formula I, II, III, IV, and V are as described above. In certainembodiments, the particular compound of Formula I, II, III, IV, or V isthe compound defined by one of the embodiments described above.Promoting the activity of RORγ means to increase the activity of RORγ.In certain embodiments, exposing a RORγ to an effective amount of atetrahydro[1,8]naphthyridine or related compound described herein (suchas a compound of Formula I, II, III, IV, or V) results in an increase inRORγ activity of at least 5%, 10%, 20%, or 50% relative to the activityof RORγ under substantially the same conditions but without the presenceof the tetrahydro[1,8]naphthyridine or related compound.

Further, it is contemplated that tetrahydro[1,8]naphthyridine andrelated compounds described herein, such as a compound of Formula I, II,III, IV, or V, can increase the amount of interleukin-17 (IL-17) in asubject. IL-17 is a cytokine that affects numerous biological functions.Accordingly, another aspect of the invention provides a method ofincreasing the amount of IL-17 in a subject. The method comprisesadministering to a subject an effective amount of atetrahydro[1,8]naphthyridine or related compound described herein, suchas a compound of Formula I, II, III, IV, or V, to increase the amount ofIL-17 in the subject, wherein Formula I, II, III, IV, and V are asdescribed above. In certain embodiments, the particular compound ofFormula I, II, III, IV, or V is the compound defined by one of theembodiments described above.

In certain embodiments, the subject is a human. In certain embodiments,administering the compound increases the amount of IL-17 produced byTh-17 cells in the subject. A change in the amount of IL-17 produced by,for example, Th-17 cells can be measured using procedures described inthe literature, such as an ELISA assay or intracellular staining assay.

Further, it is contemplated that tetrahydro[1,8]naphthyridine andrelated compounds described herein, such as a compound of Formula I, II,III, IV, or V, may increase the synthesis of IL-17 in a subject.Accordingly, another aspect of the invention provides a method ofincreasing the synthesis of IL-17 in a subject. The method comprisesadministering to a subject an effective amount of a compound describedherein, e.g., a compound of Formula I, II, III, IV, or V, to increasethe synthesis of IL-17 in the subject, wherein Formula I, II, III, IV,and V are as described above. In certain embodiments, the particularcompound of Formula I, II, III, IV, or V is a compound defined by one ofthe embodiments described above.

The description above describes multiple embodiments providingdefinitions for variables used herein. The application specificallycontemplates all combinations of such variables, e.g., particularcombinations of the definitions set forth for variables A and X.

III. Combination Therapy

Another aspect of the invention provides for combination therapy.Tetrahydro[1,8]naphthyridine and related compounds (e.g., a compound ofFormula I, II, III, IV, or V) or their pharmaceutically acceptable saltsmay be used in combination with additional therapeutic agents to treatmedical disorders, such as a cancer, bacterial infection, fungalinfection, and immune deficiency disorder.

Exemplary therapeutic agents that may be used as part of a combinationtherapy in treating cancer, include, for example, mitomycin, tretinoin,ribomustin, gemcitabine, vincristine, etoposide, cladribine,mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin,nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed,daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane,nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone,aminoglutethimide, amsacrine, proglumide, elliptinium acetate,ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin,nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane,sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine,picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride,oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol,formestane, interferon-alpha, interferon-2 alpha, interferon-beta,interferon-gamma, colony stimulating factor-1, colony stimulatingfactor-2, denileukin diftitox, interleukin-2, and leutinizing hormonereleasing factor.

Exemplary therapeutic agents that may be used as part of a combinationtherapy in treating a bacterial infection, include, for example,amoxicillin, azithromycin, cefazolin, ceftriaxone, cefuroxime,cephalexin, ciprofloxacin, clindamycin, doxycycline, levofloxacin,linezolid, metronidazole, moxifloxacin, and penicillin.

Exemplary therapeutic agents that may be used as part of a combinationtherapy in treating a fungal infection, include, for example,2-phenylphenol; 8-hydroxyquinoline sulphate; acibenzolar-S-methyl;aldimorph; amidoflumet; ampropylfos; ampropylfos-potassium; andoprim;anilazine; azaconazole; azoxystrobin; benalaxyl; benodanil; benomyl;benthiavalicarb-isopropyl; benzamacril; benzamacril-isobutyl; bilanafos;binapacryl; biphenyl; bitertanol; blasticidin-S; bromuconazole;butylamine; calcium polysulphide; capsimycin; captafol; captan;carbendazim; carboxin; carpropamid; carvone; chinomethionat;chlobenthiazone; chlorfenazole; chloroneb; chlorothalonil; chlozolinate;clozylacon; cyazofamid; cyflufenamid; cymoxanil; cyproconazole;cyprodinil; cyprofuram; Dagger G; debacarb; dichlofluanid; dichlone;dichlorophen; diclocymet; diclomezine; dicloran; diethofencarb;difenoconazole; diflumetorim; dimethirimol; dimethomorph; dimoxystrobin;diniconazole; diniconazole-M; dinocap; diphenylamine; dipyrithione;ditalimfos; dithianon; dodine; drazoxolon; edifenphos; epoxiconazole;ethaboxam; ethirimol; etridiazole; famoxadone; fenamidone; fenapanil;fenarimol; fenbuconazole; fenfuram; fenhexamid; fenitropan; fenoxanil;fenpiclonil; fenpropidin; fenpropimorph; ferbam; fluazinam;flubenzimine; fludioxonil; flumetover; flumorph; fluoromide;fluoxastrobin; fluquinconazole; flurprimidol; flusilazole;flusulphamide, hexaconazole; hymexazole; imazalil; imibenconazole;iminoctadine triacetate; iminoctadine tris(albesil); iodocarb;ipconazole; iprobenfos; iprodione; iprovalicarb; irumamycin;isoprothiolane; isovaledione; kasugamycin; kresoxim-methyl; oxyfenthiin;paclobutrazole; pefurazoate; penconazole; pencycuron; phosdiphen;phthalide; picoxystrobin; piperalin; polyoxins; polyoxorim; probenazole;prochloraz; procymidone; propamocarb; propanosine-sodium; propiconazole;propineb; proquinazid; prothioconazole; pyraclostrobin; pyrazophos;pyrifenox; pyrimethanil; pyroquilon; pyroxyfur; pyrrolenitrine;tetraconazole; thiabendazole; thicyofen; thifluzamide;thiophanate-methyl; thiram; tioxymid; tricyclazole; tridemorph;trifloxystrobin; triflumizole; triforine; triticonazole; uniconazole;validamycin A; vinclozolin; zineb; ziram; and zoxamide.

The amount of tetrahydro[1,8]naphthyridine or related compound (e.g., acompound of Formula I, II, III, IV, or V) and additional therapeuticagent and the relative timing of administration may be selected in orderto achieve a desired combined therapeutic effect. For example, whenadministering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like.Further, for example, a tetrahydro[1,8]naphthyridine or related compound(e.g., a compound of any one of Formula I, II, III, IV, or V) may beadministered during a time when the additional therapeutic agent(s)exerts its prophylactic or therapeutic effect, or vice versa.

The doses and dosage regimen of the active ingredients used in thecombination therapy may be determined by an attending clinician. Incertain embodiments, the tetrahydro[1,8]naphthyridine or relatedcompound (e.g., a compound of any one of Formula I, II, III, IV, or V)and the additional therapeutic agent(s) are administered in dosescommonly employed when such agents are used as monotherapy for treatingthe disorder. In other embodiments, the tetrahydro[1,8]naphthyridine orrelated compound (e.g., a compound of any one of Formula I, II, III, IV,or V) and the additional therapeutic agent(s) are administered in doseslower than the doses commonly employed when such agents are used asmonotherapy for treating the disorder. In certain embodiments, thetetrahydro[1,8]naphthyridine or related compound (e.g., a compound ofany one of Formula I, II, III, IV, or V) and the additional therapeuticagent(s) are present in the same composition, which is suitable for oraladministration.

In certain embodiments, the tetrahydro[1,8]naphthyridine or relatedcompound (e.g., a compound of any one of Formula I, II, III, IV, or V)and the additional therapeutic agent(s) may act additively orsynergistically. A synergistic combination may allow the use of lowerdosages of one or more agents and/or less frequent administration of oneor more agents of a combination therapy. A lower dosage or less frequentadministration of one or more agents may lower toxicity of the therapywithout reducing the efficacy of the therapy.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of the tetrahydro[1,8]naphthyridine or related compound(e.g., a compound of any one of Formula I, II, III, IV, or V), apharmaceutically acceptable carrier, vehicle or diluent, and optionallyat least one additional therapeutic agent listed above.

IV. Pharmaceutical Compositions and Dosing Considerations

As indicated above, the invention provides pharmaceutical compositions,which comprise a therapeutically-effective amount of one or more of thecompounds described above, formulated together with one or morepharmaceutically acceptable carriers (additives) and/or diluents. Thepharmaceutical compositions may be specially formulated foradministration in solid or liquid form, including those adapted for thefollowing: (1) oral administration, for example, drenches (aqueous ornon-aqueous solutions or suspensions), tablets, e.g., those targeted forbuccal, sublingual, and systemic absorption, boluses, powders, granules,pastes for application to the tongue; (2) parenteral administration, forexample, by subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; (3) topical application, for example, asa cream, ointment, or a controlled-release patch or spray applied to theskin; (4) intravaginally or intrarectally, for example, as a pessary,cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8)nasally.

The phrase “therapeutically-effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect in at least a sub-population of cells in an animal ata reasonable benefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, out of one hundred percent, this amount will range from about0.1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,celluloses, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present invention. In certain embodiments, an aforementionedformulation renders orally bioavailable a compound of the presentinvention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds and surfactants, such as poloxamer and sodium laurylsulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, zinc stearate, sodium stearate, stearic acid, and mixturesthereof; (10) coloring agents; and (11) controlled release agents suchas crospovidone or ethyl cellulose. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-shelled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99% (morepreferably, 10 to 30%) of active ingredient in combination with apharmaceutically acceptable carrier.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administrations are preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Preferably, the compounds areadministered at about 0.01 mg/kg to about 200 mg/kg, more preferably atabout 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5mg/kg to about 50 mg/kg. When the compounds described herein areco-administered with another agent (e.g., as sensitizing agents), theeffective amount may be less than when the agent is used alone.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. Preferred dosing is one administrationper day.

The invention further provides a unit dosage form (such as a tablet orcapsule) comprising a tetrahydro[1,8]naphthyridine or related compounddescribed herein (such as a compound of any one of Formulae I-V or aspecific compound described herein, such as in Tables 1-3) in atherapeutically effective amount for the treatment of an immune orinflammatory disorder, such as one of the particular immune disorders orinflammatory disorders described herein.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1 Synthesis of2,6-Difluoro-N-(8-(4-fluorobenzenesulfonyl)-5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)benzamide(1)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of [1,8]-Naphthyridin-2-ylamine

Pyridine-2,6-diamine (0.30 g, 2.8 mmol), 3-dimethylaminoacrolein (90%,0.30 g, 2.8 mmol), and polyphosphoric acid (PPA) (2.7 mL) were combinedand the reaction mixture was heated to 120° C. for 10 hours. Then, thereaction mixture was poured on ice water and neutralized with solidsodium carbonate. The resulting aqueous mixture was extracted threetimes with ethyl acetate and the combined organic extracts were washedwith brine, concentrated, and purified by column chromatography(EtOAc/hexanes) to give [1,8]-naphthyridin-2-ylamine Yield 85 mg (21%).LCMS (ESI): calc. C₈H₇N₃=145; obs. M+H=146.

Part II—Synthesis of 2,6-Difluoro-N-[1,8]naphthyridin-2-ylbenzamide

[1,8]-Naphthyridin-2-ylamine (85 mg, 0.59 mmol) was dissolved indichloromethane (2 mL) and pyridine (0.10 mL, 1.2 mmol).2,6-Difluorobenzoyl chloride (0.068 mL, 0.76 mmol) was then added andthe reaction mixture was stirred at room temperature for 30 minutes.Next, the reaction mixture was diluted with ethyl acetate and washedwith water followed by brine. The resulting organic solution waspurified by column chromatography (EtOAc/hexanes) to give2,6-difluoro-N-[1,8]naphthyridin-2-ylbenzamide. Yield 35 mg (21%). LCMS(ESI): calc. C₁₅H₉F₂N₃O=285; obs. M+H=286.

Part III—Synthesis of2,6-Difluoro-N-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)benzamide

2,6-Difluoro-N-[1,8]naphthyridin-2-ylbenzamide (35 mg, 0.12 mmol) and10% Pd/C (15 mg) were suspended in ethanol (5 mL). Concentrated HCl(0.02 mL, 0.24 mmol) was then added and the reaction mixture was stirredunder hydrogen (1 atmosphere) for three hours. Next, the reactionmixture was filtered through Celite and concentrated to give2,6-difluoro-N-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)benzamide.Yield 33 mg (95%). LCMS (ESI): calc. C₁₅H₁₃F₂N₃O=289; obs. M+H=290.

Part IV—Synthesis of2,6-Difluoro-N-(8-(4-fluorobenzenesulfonyl)-5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)benzamide

2,6-Difluoro-N-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)benzamide (30mg, 0.10 mmol) was dissolved in dichloromethane (0.3 mL) and pyridine(0.025 mL, 0.31 mmol). 4-Fluorobenzenesulfonyl chloride (23 mg, 0.12mmol) was then added and the reaction mixture was stirred at roomtemperature for 12 hours. Next, the reaction mixture was washed with 1MHCl(aq), sat′d NaHCO₃(aq), and brine. The resulting organic solution wasconcentrated, dissolved in DMSO, and purified by HPLC to give2,6-difluoro-N-(8-(4-fluorobenzenesulfonyl)-5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl]benzamide.¹H NMR 250 MHz CDCl₃ δ 8.13 (bs, 1H), 8.03 (dd, J=7.9, 4.3 Hz, 2H), 7.83(d, J=7.9 Hz, 1H), 7.48 (p, J=6.5 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.15(t, J=7.9 Hz, 2H), 7.06 (t, J=7.8 Hz, 2H), 4.07 (dd, J=5.8, 4.3 Hz, 2H),2.76 (t, J=6.5 Hz, 2H), 2.06 (p, J=5.8 Hz, 2H). LCMS (ESI): calc.C₂₁H₁₆F₃N₃O₃S=447; obs. M+H=448.

Example 2 Synthesis of2,6-Dichloro-N-[4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl]-benzamide(2)

Part I—Synthesis of (6-Bromo-2-nitropyridin-3-yloxy)acetic acid methylester

6-Bromo-2-nitropyridin-3-ol (10.8 g, 49.1 mmol) was dissolved indimethylsulfoxide (DMSO) (30 mL). Potassium carbonate (13.6 g, 98.6mmol) and bromoacetic acid methyl ester (7.0 mL, 74 mmol) were added andthe reaction mixture was stirred at 60° C. for two hours. Then, thereaction mixture was cooled to room temperature and neutralized with 1NHCl(aq). The aqueous solution was extracted twice with ethyl acetate,and the combined organic extracts were washed with brine. The productwas purified by column chromatography (SiO₂, EtOAc/hexanes) to afford(6-bromo-2-nitropyridin-3-yloxy)acetic acid methyl ester. Yield 10.9 g(37.5 mmol, 76%). LCMS (ESI): calc. C₈H₇BrN₂O₅=290, 292; obs. Lowionization.

Part II—Synthesis of (2-Amino-6-bromopyridin-3-yloxy)acetic acid methylester

(6-Bromo-2-nitropyridin-3-yloxy)acetic acid methyl ester (10.9 g, 37.5mmol) was dissolved in methanol (90 mL). Concentrated HCl (10 mL) wasthen added followed by iron (6.4 g, 110 mmol). The reaction mixture wasstirred at 60° C. for 1 hour. Then, the reaction mixture was cooled toroom temperature and neutralized with solid sodium bicarbonate. Theinsoluble iron salts were removed by centrifugation. Silica gel was thenadded to the supernatant and the solvents were removed under reducedpressure. The resulting crude material was purified by columnchromatography (SiO₂, EtOAc/hexanes) to give(2-amino-6-bromopyridin-3-yloxy)acetic acid methyl ester. Yield 4.0 g(15 mmol, 40%). LCMS (ESI): calc. C₈H₉BrN₂O₃=260, 262; obs. M+H=261,263.

Part III—Synthesis of 6-Bromo-4H-pyrido[3,2-b][1,4]oxazine-3-one

(2-Amino-6-bromopyridin-3-yloxy)acetic acid methyl ester (4.0 g, 15mmol) was dissolved in MeOH (40 mL). K₂CO₃ (3.0 g, 22 mmol) was addedand the reaction was stirred at 70° C. for 1 hour. Then, the solvent wasremoved under reduced pressure and the resulting slurry was suspended indichloromethane (DCM) and washed with H₂O and then brine. The organiclayer was dried (Na₂SO₄) and the product was precipitated from DCM/Et₂Oto give 6-bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one. Yield 1.9 g (8.3mmol, 55%). LCMS (ESI): calc. C₇H₅BrN₂O₂=228, 230; obs. M+H=229, 231.

Part IV—Synthesis of 6-Bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (1.35 g, 5.89 mmol) wasdissolved in THF (40 mL). Boranedimethylsulphide complex (2.0 M in THF,5.89 mL, 11.79 mmol) was added and the resulting mixture heated to 70°C. under nitrogen for 15 minutes. Next, the reaction mixture was cooledto room temperature, quenched with methanol (˜5 mL), and then driedunder vacuum to obtain a white solid. The crude material was dissolvedin dichloromethane and washed with H₂O. The aqueous phase was discardedand the organic phase was dried under vacuum to give6-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. Yield: 1.1 g (87%).LCMS (ESI): calc. C₇H₇BrN₂O=214, 216; obs. M+H=215, 217.

Part V—Synthesis of6-Bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

6-Bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (1.0 g, 4.65 mmol) andm-tolylsulfonyl chloride were dissolved in pyridine (10 mL). Theresulting mixture was stirred at 80° C. for one hour. An additionalportion of m-tolylsulfonyl chloride (0.98 g, 5.12 mmol) was added andthe reaction mixture was stirred at 80° C. for 16 hours. Next, excesssolvent was removed under vacuum, and the resulting oil was trituratedwith water to obtain a tan solid, which was collected by vacuumfiltration and washed with water and diethyl ether to give6-bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine.Yield 1.3 g (76%). LCMS (ESI): calc. C₁₋₄H₁₃BrN₂O₃S=368, 370; obs.M+H=369, 371.

Part VI—Synthesis of4-(Toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamine

6-Bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine(300 mg, 0.81 mmol) was dissolved in p-dioxane (10 mL), followed bybenzophenone imine (409 μL, 2.44 mmol), sodium tert-butoxide (207 mg,2.15 mmol), XantPhos (70 mg, 0.12 mmol), and finally Pd₂(dba)₃ (74 mg,0.08 mmol). The resulting mixture was heated to 100° C. for 2.5 hours.Then, the reaction mixture was concentrated under vacuum and partitionedin a mixture of ethyl acetate and water. The aqueous phase wasdiscarded, and the organic phase was concentrated and purified by flashchromatography (12 g silica column, 0-60% EtOAc/Hexane) to give4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamineYield 80 mg (32%). LCMS (ESI): calc. C₁₄H₁₅N₃O₃S=305; obs. M+H=306.

Part VII—Synthesis of2,6-Dichloro-N-[4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl]-benzamide

4-(Toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamine(20 mg, 0.065 mmol) was dissolved in p-dioxane (0.400 mL) and water(0.100 mL), followed by 2,6-dichlorobenzoyl chloride (21 μL, 0.098 mmol)and NaHCO₃ (11 mg, 0.13 mmol). The resulting mixture was stirred at roomtemperature for 15 hours, concentrated under vacuum, and purified byHPLC to give2,6-dichloro-N-[4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl]-benzamide.LCMS (ESI): calc. C₂₁H₁₇Cl₂N₃O₄S=477; obs. M+H=478.

Example 3 Synthesis of2-Phenyl-N-[4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl]-propionamide(3)

4-(Toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamine(20 mg, 0.065 mmol) was dissolved in N-methylpyrrolidinone (0.5 mL),followed by (d,l)-2-phenylpropionic acid (30 μL, 0.11 mmol), HATU (45mg, 0.12 mmol), and diisopropyl ethylamine (23 μL, 0.13 mmol). Thereaction mixture was stirred at room temperature for 18 hours. Then, thereaction mixture was then purified by HPLC to give2-phenyl-N-[4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl]-propionamide.LCMS (ESI): calc. C₂₃H₂₃N₃O₄S=437; obs. M+H=438.

Example 4 Synthesis of6-(Benzyloxy)-4-m-tolylsulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine(4)

To6-bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine(50 mg, 140 mmol) in benzyl alcohol (400 μL) was added CuI (15 mg, 79mmol), 1,10-phenanthroline (15 mg, 83 mmol), and Cs₂CO₃ (70 mg, 210mmol). The resulting mixture was heated to 130° C. for 2 hours. Next,the reaction mixture was cooled to room temperature and quenched with asmall amount of water, then extracted with ethyl acetate. The aqueousphase was discarded and the organic phase concentrated under reducedpressure. The resulting residue was purified by HPLC to afford6-benzyloxy-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine.LCMS (ESI): calc. C₂₁H₂₀N₂O₄S=396; obs. M+H=397.

Example 5 Synthesis of6-(2,6-Dichlorobenzyloxy)-4-m-tolylsulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine(5)

To6-bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine(50 mg, 140 mmol) in 2,6-dichlorobenzyl alcohol (400 μL) was added CuI(15 mg, 79 mmol), 1,10-phenanthroline (15 mg, 83 mmol), and Cs₂CO₃ (70mg, 210 mmol). The resulting mixture was heated to 130° C. for 2 hours.Next, the reaction mixture was cooled to room temperature and quenchedwith a small amount of water, then extracted with ethyl acetate. Theaqueous phase was discarded and the organic phase was concentrated underreduced pressure. The resulting residue was purified by HPLC to give6-(2,6-dichloro-benzyloxy)-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2b][1,4]oxazine.LCMS (ESI): calc. C₂₁H₁₈Cl₂N₂O₄S=464; obs. M+H=465.

Example 6 Synthesis of6-(1-Phenylethoxy)-4-m-tolylsulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine(6)

To6-bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine(50 mg, 140 mmol) in (d,l)-1-phenylethanol (400 μL) was added CuI (15mg, 79 mmol), 1,10-phenanthroline (15 mg, 83 mmol), and Cs₂CO₃ (70 mg,210 mmol). The resulting mixture was heated to 130° C. for 2 hours.Next, the reaction mixture was cooled to room temperature and quenchedwith a small amount of water, then extracted with ethyl acetate. Theaqueous phase was discarded and the organic phase was concentrated underreduced pressure. The resulting residue was purified by HPLC to give6-(1-phenyl-ethoxy)-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. LCMS(ESI): calc. C₂₂H₂₂N₂O₄S =410; obs. M+H =411.

Example 7 Biological Assays for RORγ Activity

Exemplary compounds from the above Examples were tested for ability toincrease RORγ activity using a RORγ-Ligand Binding Domain (LBD) TR-FRETAssay. Assay procedures and results are described below.

Part I—Procedures for RORγ-Ligand Binding Domain TR-FRET Assay

Recombinant, HIS-tagged RORγ-LBD was expressed in SF9 cells using abaculovirus expression system. Cells were lysed and the lysate was usedas a source for RORγ-LBD for the assay. A 1:80 dilution of RORγ-LBDlysate in assay buffer (25 mM HEPES pH 7.0, 100 mM NaCl, 0.01% Tween,0.1% BSA) was prepared and 5 μL was added to each well (RORγ-LBD finalconcentration ˜3 nM). Control wells received lysate from SF9 cells notexpressing RORγ-LBD.

Compounds to be tested were diluted to 100× final test concentration inDMSO and further diluted to 4× final test concentration using assaybuffer to provide the test compound mixture. An aliquot (5 μL) of thetest compound mixture was added to each well.

A 4× stock of biotinylated-LXXLL peptide from SRC1-2(Biotin-CPSSHSSLTERHKILHRLLQEGSPS) was prepared in assay buffer and a 5μL aliquot added to each well (450 nM final concentration). A 4×solution of europium tagged anti-HIS antibody (2 nM final concentration)and APC conjugated streptavidin (60 nM final concentration) wereprepared and a 5 μL aliquot added to each well.

The final assay mixture was incubated for 4 hours to overnight, and thefluorescence signal was measured on an Envision plate reader:(Excitation filter=340 nm; APC emission=665 nm; Europium emission=615nm; dichroic mirror=D400/D630; delay time=100 μs, integration time=200μs).

EC₅₀ values for test compounds were calculated from the quotient of thefluorescence signal at 665 nm divided by the fluorescence signal at 615nm using GraphPad Prism software.

Part III—Results

Compounds 1-6 from the above Examples were tested. Compounds 1-5 weredetermined to have an EC₅₀ less than or equal 15 μM. No promotion ofRORγ activity was detected for compound 6 during the assay measuringEC₅₀ values less than or equal to 20 μM.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

We claim:
 1. A compound represented by Formula I:

or a pharmaceutically acceptable salt or solvate thereof; wherein: A isaryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,—N(R⁴)(R⁵), —CO₂R⁶, —C(O)R⁶, —CN, —C₁₋₄alkylene-C₁₋₄alkoxy,—C₁₋₄alkylene-N(R⁴)(R⁵), —C₁₋₄alkylene-CO₂R⁶, —O—C₁₋₆alkylene-N(R⁴)(R⁵),—N(R⁴)C(O)—C₁₋₆alkylene-N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵),—N(R⁴)SO₂(C₁₋₆alkyl), —C(O)N(R⁴)(R⁵), and —N(R⁴)C(O)N(R⁴)(R⁵); X is—C(R⁶)₂—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)-ψ or —C(O)—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)-ψ,wherein ψ is a bond to the sulfonamide ring nitrogen atom in Formula I;Y is —N(R²)(R³) or —O-aralkyl, wherein said aralkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN, —CO₂—C₁₋₆alkyl,—C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl, —SO₂N(R⁴)(R⁵), and—N(R⁴)SO₂(C₁₋₆alkyl); R¹ represents independently for each occurrencehydrogen, halogen, or C₁₋₆alkyl; R² is —C(O)-aryl, —C(O)-aralkyl,—C(O)—[C(R⁶)₂]_(m)-cycloalkyl, —C(O)—[C(R⁶)₂]_(m)-heterocyclyl,—C(O)—C₁₋₈alkyl, —C(O)—C₁₋₆alkylene-C₁₋₆alkoxyl,—C(O)—C₁₋₆alkylene-cycloalkyl, or —C(O)—C₁₋₆alkylene-heterocycloalkyl;each of which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl,—SO₂N(R⁴)(R⁵), and —N(R⁴)SO₂(C₁₋₆alkyl); R³ is hydrogen or C₁₋₆alkyl; R⁴and R⁵ each represent independently for each occurrence hydrogen orC₁₋₆alkyl; or R⁴ and R⁵ taken together with the nitrogen atom to whichthey are attached form a 3-7 membered heterocyclic ring; R⁶ representsindependently for each occurrence hydrogen or C₁₋₆alkyl; R⁷ is hydrogen,hydroxyl, C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl, —CO₂R⁶,C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(⁴)CO₂—C₁₋₆alkyl, or C₁₋₆alkylene-N(R⁴)(C(O)N(R⁴)(R⁵); or R⁷ isheterocycloalkyl or C₁₋₄alkylene-heterocycloalkyl, wherein theheterocycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of oxo, halogen,hydroxyl, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy; R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl,C₁₋₆alkylene-N(R⁴)(R⁵), or C₁₋₆alkylene-N(R⁴)C(O)—C₁₋₆alkyl; n is 1 or2; and m and p each represent independently for each occurrence 0, 1, or2.
 2. The compound of claim 1, wherein A is phenyl optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy.
 3. The compound of claim 1, wherein A is heteroaryloptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxy, and C₁₋₆haloalkoxy.
 4. The compound of claim 1, wherein X is—C(R⁶)₂—[C(R⁶)(R⁷)]—[C(R⁶)₂]_(m)-ψ.
 5. The compound of claim 1, whereinY is —N(R²)(R³).
 6. The compound of claim 5, wherein R² is —C(O)-aryl or—C(O)-aralkyl; each of which is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, andC₁₋₆haloalkyl.
 7. The compound of claim 5, wherein R² is —C(O)-phenyl or—C(O)-benzyl; each of which is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, and C₁₋₆haloalkyl.
 8. The compound of claim 1,wherein Y is —O-aralkyl optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, hydroxyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl,—N(R⁴)(R⁵), —CN, —CO₂—C₁₋₆alkyl, and —C(O)—C₁₋₆alkyl.
 9. The compound ofclaim 1, wherein Y is —O-benzyl optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, and C₁₋₆haloalkyl.
 10. The compound of claim 6,wherein R⁷ is hydrogen.
 11. The compound of claim 6, wherein R⁷ isC₁₋₃hydroxyalkyl, methyl, ethyl, or C₁₋₃alkylene—N(H)C(O)—C₁₋₄alkyl. 12.The compound of claim 1, wherein the compound is represented by FormulaIII:

or a pharmaceutically acceptable salt or solvate thereof; wherein: A isaryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each ofwhich is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,—N(R⁴)(R⁵), —CO₂R⁶, —C(O)R⁶, —CN, —C₁₋₄alkylene-C₁₋₄alkoxy, and—C₁₋₄alkylene-N(R⁴)(R⁵); Y is —N(R²)(R³) or —O-aralkyl, wherein saidaralkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl,—SO₂N(R⁴)(R⁵), and —N(R⁴)SO₂(C₁₋₆alkyl); R¹ is hydrogen, halogen, orC₁₋₆alkyl; R² is —C(O)-aryl, —C(O)-aralkyl,—C(O)—[C(R⁶)₂]_(m)-cycloalkyl, —C(O)—[C(R⁶)₂]_(m)-heterocyclyl,—C(O)—C₁₋₈alkyl, —C(O)—C₁₋₆alkylene-C₁₋₆alkoxyl,—C(O)—C₁₋₆alkylene-cycloalkyl, or —C(O)—C₁₋₆alkylene-heterocycloalkyl;each of which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁴)(R⁵), —CN,—CO₂—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, —C(O)N(R⁴)(R⁵), —S(O)_(p)C₁₋₆alkyl,—SO₂N(R⁴)(R⁵), and —N(R⁴)SO₂(C₁₋₆alkyl); R³ is hydrogen or C₁₋₆alkyl; R⁴and R⁵ each represent independently for each occurrence hydrogen orC₁₋₆alkyl; or R⁴ and R⁵ taken together with the nitrogen atom to whichthey are attached form a 3-7 membered heterocyclic ring; R⁶ representsindependently for each occurrence hydrogen or C₁₋₆alkyl; R⁷ is hydrogen,hydroxyl, C₁₋₆hydroxyalkyl, C₁₋₆alkyl, C₁₋₆haloalkyl, —CO₂R⁶,C₁₋₆alkylene-CO₂R⁶, C₁₋₄hydroxyalkylene-CO₂R⁶, —N(R⁴)(R⁵),C₁₋₆alkylene-N(R⁴)(R⁵), C₁₋₆hydroxyalkylene-N(R⁴)(R⁵), —N(R⁴)C(O)R⁹,C₁₋₆alkylene-N(R⁴)C(O)R⁹, C₁₋₆alkylene-C(O)N(R⁴)(R⁵),—N(R⁴)CO₂—C₁₋₆alkyl, or C₁₋₆alkylene-N(R⁴)(C(O)N(R⁴)(R⁵); or R⁷ isheterocycloalkyl or C₁₋₄alkylene-heterocycloalkyl, wherein theheterocycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of oxo, halogen,hydroxyl, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆alkoxy, andC₁₋₆haloalkoxy; R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆hydroxyalkyl,C₁₋₆alkylene-N(R⁴)(R⁵), or C₁₋₆alkylene-N(R⁴)C(O)—C₁₋₆alkyl; and m and peach represent independently for each occurrence 0, 1, or
 2. 13. Thecompound of claim 12, wherein A is phenyl optionally substituted with 1,2, or 3 substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, and C₁₋₆haloalkoxy. 14.The compound of claim 13, wherein Y¹ is —N(R²)(R³).
 15. The compound ofclaim 14, wherein R² is —C(O)-aryl or —C(O)-aralkyl; each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, C₁₋₆alkyl, and C₁₋₆haloalkyl.
 16. The compound of claim14, wherein R² is —C(O)-phenyl or —C(O)-benzyl; each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, C₁₋₆alkyl, andC₁₋₆haloalkyl.
 17. The compound of claim 15, wherein R⁷ is hydrogen. 18.The compound of claim 15, wherein R⁷ is C₁₋₆hydroxyalkyl, C₁₋₆alkyl,C₁₋₆alkylene-CO₂R⁶, —N(R⁴)(R⁵), C₁₋₆alkylene-N(R⁴)(R⁵), orC₁₋₆alkylene-N(R⁴)C(O)R⁹.
 19. A compound in Table 1A, 2A, or 3A below ora pharmaceutically acceptable salt thereof: TABLE 1A

No. Y Z I-1 

I-2 

I-3 

I-4 

I-5 

I-6 

I-7 

I-8 

I-9 

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

TABLE 2A

No. Y

Z II-1

II-2

II-3

II-4

II-5

II-6

II-7

II-8

II-9

 II-10

 II-26

 II-27

 II-28

 II-29

 II-30

 II-31

TABLE 3A No. Compound III-27

III-28

III-33

III-34

III-35

III-36

III-37

III-38

III-39

III-41

III-42

III-43

III-44

III-45

III-40

III-47

III-46

III-50


20. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 21. A method of treating a disorderselected from the group consisting of cancer, bacterial infection, andfungal infection, comprising administering a therapeutically effectiveamount of a compound of claim 1 to a subject in need thereof, whereinthe cancer is colon cancer, pancreatic cancer, breast cancer, ovariancancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma,adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lungcancer, leukemia, bladder cancer, stomach cancer, cervical cancer,testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidneycancer, uterus cancer, espophagus cancer, liver cancer, an acousticneuroma, oligodendroglioma, meningioma, neuroblastoma, orretinoblastoma.
 22. The method of claim 21, wherein the disorder iscolon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostatecancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma,sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia,bladder cancer, stomach cancer, cervical cancer, testicular cancer, skincancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer,espophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma,meningioma, neuroblastoma, or retinoblastoma.
 23. A method of increasingthe amount of IL-17 in a subject, comprising administering to a subjectan effective amount of a compound of claim 1 to increase the amount ofIL-17 in the subject.
 24. The method of claim 21, wherein the subject isa human.
 25. A method of promoting the activity of RORγ, comprisingexposing a RORγ to an effective amount of a compound of claim 1 topromote the activity of said RORγ.